Aryl and heteroaryl compounds, compositions, and methods of use

ABSTRACT

This invention provides aryl and heteroaryl compounds of Formula (I) as described herein, and methods of their preparation. Also provided are pharmaceutical compositions made with the compounds of Formula (I) and methods for making such compositions. Compounds of Formula (I) may be useful for treating viral infections including orthopox viruses, either alone or in combination with other therapeutic agents.

STATEMENT OF RELATED APPLICATIONS

The present application claims priority under 35 USC 119 from thefollowing U.S. Provisional Patent Applications: Ser. No. 60/493,879,filed Aug. 8, 2003, entitled “Aryl and Heteroaryl Compounds as Antviralagents”; Ser. No. 60/493,878, filed Aug. 8, 2003, entitled “Aryl andHeteroaryl Componds and Methods to Modulate Red Blood Cell Production”;Ser. No. 60/493,903, filed Aug. 8, 2003, entitled “Aryl and HeteroarylCompounds and Methods to Modulate Coagulation”, which are hereinincorporated by reference in their entireties.

FIELD OF THE INVENTION

This invention relates to aryl and heteroaryl compounds and compositionsthat may possess antiviral activity, and methods of use of suchcompounds and compositions.

BACKGROUND OF THE INVENTION

Viruses may infect cells to take over the host cell machinery andproduce new viral particles via transcription and translation processes.Interception of either of these processes, including pre- and posttranslation events, may cripple virus propagation.

Since the discovery of non-nucleoside reverse transcriptase inhibitors(NNRTI), and protease inhibitors (PI), nonnucleoside organic moleculeshave been designed to combat viral infections by inhibiting a variety oftargets responsible for viral replication. Examples of such targetsinclude reverse transcriptases, DNA polymerases, viral proteases (e.g.,serine, cysteine, aspartyl, metalloproteases), integrases, helicases,fusion proteins, chemokines (CCR5, CXCR4), and chemokine receptors. Forexample, there are drugs which may prevent fusion of the viral envelopewith the cell membrane and therefore inhibit the entry of viruses, suchas human immunodeficiency virus (HIV), into the cell. Also, other drugsmay act at the late stage of the viral replication cycle to preventpropagation of virus that is already in the cell.

Smallpox is a member of the highly homologous orthopox family ofviruses. As of the 1990s, it was belileved that smallpox virus was nolonger a health concern as the last known case of smallpox had occurredin 1977. Also, universal vaccination programs in the U.S. werediscontinued in 1972 because the risk of complications from the vaccinewas actually greater than the risk of being infected with the disease.Recently, however, cases of smallpox have been documented. In addition,due to the highly homologous nature of the orthopox family, therapeuticsdeveloped against smallpox are also potential candidate therapies forrelated viruses that continue to plague society such as monkeypox, avirus that recently reemerged in the Africa and spread to the US throughexotic animals, and mulluscipox virus, which results in a commoncutaneous infection that may be problematic with immunocompromisedindividuals. Thus, there is a renewed interest in developing antiviralagents to treat orthopox viruses, and more particularly, smallpox.

A wide spectrum of antiviral agents have been investigated usingdifferent strains of variola as well as other orthopoxviruses (Baker, etal., Antiviral research, 57, 13, 2003). Among antiviral compounds foundto be useful were cidofovir (DNA polymerase), ribavrin and tiazofurin(IMP dehydrogenase), C-ca3-ADO, and C3-Npc-A (SAH hydrolase). Also,HPMPC (Cidofovir), a DNA Polymerase Inhibitor for the treatment of CMVretinitis in AIDS patients, may have therapeutic potential for treatmentof various other herpes viruses, as well as polyomavirus,papillomavirus, adenovirus as well as poxvirus. For example, in vitroevidence demonstrates that HPMPC may be active against all poxvirusesstudied to date as well as vaccinia and cowpox virus infections.However, treatment with HPMPC is only currently available in eithertopical or intravenous forms. Also, side effects, including significantnephrotoxicity, may result.

While useful anti-viral compounds have been identified, viruses canrapidly acquire resistance to drugs. Thus, new anti-viral agents areneeded that can be used alone or in a cocktail of drugs where thecocktail can cripple a virus by hitting a multitude of targets.

SUMMARY OF THE INVENTION

Embodiments of the present invention provide aryl and heteroarylcompounds, compositions, and methods of use of such compounds andcompositions. The present invention may be embodied in a variety ofways.

In one embodiment, the present invention provides compounds of Formula(I) as described herein. In another embodiment, the present inventionprovides methods for the preparation of compounds of Formula (I).

The present invention also provides pharmaceutical compositionscomprising compounds of Formula (I). In another embodiment, the presentinvention also provides methods for the preparation of compositionscomprising the compounds of Formula (I). The pharmaceutical compositionsmay comprise pharmaceutically acceptable carriers, excipients, and/ordiluents.

In another embodiment, the present invention provides methods for theuse of compounds of Formula (I) and pharmaceutical compositionscomprising compounds of Formula (I). In one embodiment, the compoundsand pharmaceutical compositions of the present invention may be used fortreating human or animal disorders. For example, the compounds andpharmaceutical compositions of the present invention may be used fortreating or preventing viral infection in a subject. Compounds ofFormula (I) may be useful in a variety of applications includingtreating or preventing viral infections in a subject such as, but notlimited to, orthopox infections including smallpox, vaccinia virus,monkey pox, or cowpox viral infections. Thus, in one embodiment, thecompounds and pharmaceutical compositions of the present invention maybe used for treating or preventing orthopox viral infection in asubject. In an example embodiment, the the compounds and pharmaceuticalcompositions of the present invention may be used for treating orpreventing smallpox viral infection.

The compounds and pharmaceutical compositions of the present inventionmay provide a number of advantages when used for treating human oranimal disorders. In one embodiment, the compounds and pharmaceuticalcompositions of the present invention may provide a variety of treatmentoptions. As small molecule therapeutics, example embodiments of thecompounds and pharmaceutical compositions of the present invention maybe administered orally, topically, or parentally. Also, the compoundsand pharmaceutical compositions of the present invention may comprise aprimary therapeutic or may be used as an adjunct to other therapeutics.For example, compounds of Formula (I) may also be useful in acombination therapy with an antiviral agent where administration of athe combination of a compound of Formula (I) and an antiviral agent mayprevents viruses from bypassing or becoming resistant to an inhibitoryeffect of a compound of Formula (I) or the antiviral agent.

Additional features of the present invention will be describedhereinafter. It is to be understood that the invention is not limited inits application to the details set forth in the foregoing or followingdescription but is capable of other embodiments and of being practicedor carried out in various ways.

DETAILED DESCRIPTION

Embodiments of the present invention provide compounds, compositions andmethods of use for such compounds. In certain embodiments, the compoundsand compositions of the present invention may be used as antiviralagents for the treatment, preventions, or amelioration of viralinfection.

Embodiments of the present invention comprise compounds of Formula (I)as depicted below. Embodiments of the present invention also comprisemethods of the preparation of compounds of Formula (I) and/orpharmaceutical compositions comprising compounds of Formula (I).

In other embodiments, the present invention provides methods for the useof compounds of Formula (I) and pharmaceutical compositions comprisingcompounds of Formula (I) in treating human or animal disorders.Compounds of Formula (I) and pharmaceutical compositions comprisingcompounds of Formula (I) may be useful in a variety of applications. Forexample, the present invention provides methods of treating orpreventing viral infections in a subject. The present invention alsoprovides methods for the preparation of compounds of Formula (I) andmethods of preparation of pharmaceutical compositions comprisingcompounds of Formula (I).

Compounds of Formula (I) may be useful in a variety of applicationsincluding treating or preventing viral infections in a subject such as,but not limited to, orthopox infections such as smallpox, vacciniavirus, monkey pox, or cowpox viral infections. Compounds of Formula (I)may also be useful in a combination therapy with an antiviral agentwhere administration of a the combination of a compound of Formula (I)and an antiviral agent may prevents viruses from bypassing or becomingresistant to an inhibitory effect of a compound of Formula (I) orantiviral agent.

Thus, in one aspect, the present invention provides compounds of Formula(I):

wherein c is equal to 0, 1, or 2; wherein the values of 0, 1, and 2comprise a direct bond, —CH₂—, and —CH₂—CH₂—, optionally substituted 1to 4 times with a substituent group, wherein said substituent group(s)or the term substituted refers to groups comprising: -alkyl, -aryl,-alkylene-aryl, -arylene-alkyl, -alkylene-arylene-alkyl, —O-alkyl,—O-aryl, or -hydroxyl. In an embodiment, c is equal to 0 or 1. Inanother embodiment, c is equal to 0.

G comprises: -hydrogen, -alkyl, -heteroaryl, -aryl, -heterocyclycl,—CH═CH—CO₂R₁, —CO₂R₁, —CH₂OR₁, —CH₂SR₁—C(O)—R₁, —C(O)NR₁R₂,—C(R₁)═N—O—R₂, —C(O)C(O)R₁, —C(O)C(O)NR₁R₂, —CH═CH—NO₂, —CH═CH—CN,—C(O)—C(O)—OR₁, an acid isostere, or an ester isostere; wherein R₁ andR₂ independently comprise: -hydrogen, -alkyl, -aryl, -alkenyl,-arylene-alkyl, -alkylene-aryl, -alkylene-arylene-alkyl, -heterocyclyl,or -heteroaryl, or when R₁ and R₂ are bonded to a nitrogen group in G,R₁ and R₂ may be taken together to form a ring having the formula—(CH₂)_(m)-Z₂-(CH₂)_(n), wherein m and n are, independently, 1, 2, 3, or4; Z₂ comprises —CH₂—, —C(O)—, —O—, —N(H)—, —S—, —S(O)—, —S(O₂)—,—CON(H)—, —NHC(O)—, —NHC(O)N(H)—, —NH(SO₂)—, —S(O₂)N(H)—, —(O)CO—,—NHS(O₂)NH—, —OC(O)—, —N(R₂₁)—, —N(C(O)R₂₁)—, —N(C(O)NHR₂₁)—,—N(S(O₂)NHR₂₁)—, —N(SO₂R₂₁)—, or —N(C(O)OR₂₁)—; wherein R₂₁ compriseshydrogen, aryl, alkyl, or alkylene-aryl; or when when R₁ and R₂ arebonded to a nitrogen group in G, R₂ may be optionally substituted with asubstituent of the formula

wherein

-   -   L₁ comprises a direct bond, alkylene, —O-alkylene-, alkylene-O—,        —NH—C(O)—, —C(O)—NH— or —NH—C(O)—NH—;    -   L₂ comprises alkyline, alkenyline, heteroaryline, aryline, or        heterocyclyline;    -   L₃ comprises —O—, —N(R₃)—, —C(O)—N(R₃)—, —C(O)—O—, —C(O)—,        —N(R₃)—C(O)—N(R₄)—, —CH═CH—CO₂R₁, —C(O)R₁, —C(O)C(O)R₁, or        —C(O)C(O)NR₁R₂;    -   L₄ comprises hydrogen, alkyl, alkenyl, alkynyl, heterocyclyl,        heteroaryl, or -alkylene-aryl;    -   L₅ comprises hydrogen, alkyl, alkenyl, alkynyl, -akylene-aryl,        -alkylene-heteroaryl, alkylene-O-alkylene-aryl,        -alkylene-S-alkylene-aryl, -alkylene-O-alkyl, -alkylene-S-alkyl,        -alkylene-NH₂, -alkylene-OH, -alkylene-SH, -alkylene-C(O)—OR₅,        -alkylene-C(O)—NR₅R₆, -alkylene-NR₅R₆, -alkylene-N(R₅)—C(O)—R₆,        -alkylene-N(R₅)—S(O₂)—-R₆; or        may be taken together to constitute a direct bond; and    -   wherein R₃, R₄, R₅, and R₆ independently comprise hydrogen,        aryl, heteroaryl, alkyl, -alkylene-aryl, or,        -alkylene-heteroaryl.

In an embodiment, G comprises: -hydrogen, —CO₂R₁, —C(O)NR₁R₂, or—C(O)R₁, wherein R₁ and R₂ independently comprise -hydrogen, -alkyl,-alkenyl, -aryl. In another embodiment, G comprises an ester isosterecomprising the substituted oxadiazole:

wherein R₇ comprises alkyl, aryl, alkylene-sulfonyl-alkyl oralkylene-sulfonyl-aryl. In another embodiment R₇ comprises an alkylgroup. In another embodiment, G comprises—hydrogen. In anotherembodiment, G comprises —CO₂R₁ wherein R₁ comprises alkyl.

V comprises: —(CH₂)_(b)—O—(CH₂)_(a)—, —(CH₂)_(b)—N(R₈)—(CH₂)_(a)—,—(CH₂)_(b)—O—, —(CH₂)_(b)—N(R₈), —(CH₂)_(a)—, —CH═CH—(R₈)— or a directbond; in which a is equal to 0, 1, or 2, b is equal to 1 or 2, and R₈comprises: -hydrogen, -alkyl, -aryl, -arylene-alkyl, -alkylene-aryl, or-alkylene-arylene-alkyl; wherein the —CH₂— groups may be optionallysubstituted 1 to 4 times with a substituent group comprising: -alkyl,-aryl, -alkylene-aryl, -arylene-alkyl, -alkylene-arylene-alkyl,—O-alkyl, —O-aryl, -hydroxyl, —S-alkyl, or —S-aryl. In an embodiment, Vcomprises: —(CH₂)_(a)—, —(CH₂)_(b)—O—(CH₂)_(a)—, or a direct bond,wherein a is equal to 1 or 2, and b is equal to 1. In anotherembodiment, V comprises: —(CH₂)_(a)— or a direct bond, wherein a isequal to 1.

X comprises: —N(R₉)—, —CON(R₉)—, —N(R₉)CO—, —N(R₉)CON(R₁₀)—,—OC(O)N(R₈)—, —SO₂N(R₉)—, —N(R₉) SO₂—, or —N(R₉)SO₂N(R₁₀)—; wherein R₉and R₁₀ independently comprise: -hydrogen, -alkyl, -aryl,-arylene-alkyl, -alkylene-aryl, -alkylene-arylene-alkyl, or—(CH₂)_(d)Y—, wherein d is equal to 0, 1, or 2, wherein Y comprises:-hydrogen, —CO₂R₁₁, —CH₂OR₁₁, —C(O)—R₁₁, —C(O)NR₁₁R₁₂, —C(R₁₁)═N—O—R₁₂,—NR₁₁R₁₂, or an acid isostere; wherein R₁₁ and R₁₂ independentlycomprise: -hydrogen, -alkyl, -aryl, -arylene-alkyl, -alkylene-aryl,-alkylene-arylene-alkyl, -heterocyclyl, or -heteroaryl. In anembodiment, X comprises: —N(R₉)—, —CON(R₉)—, —N(R₉)CO—, or—N(R₉)CON(R₁₀)—, wherein R₉ and R₁₀ independently comprise: -hydrogen,-alkyl, -aryl, -arylene-alkyl, -alkylene-aryl, or-alkylene-arylene-alkyl. In another embodiment, X comprises —N(R₉)—,—CON(R₉)—, or —N(R₉)CO—, wherein R₉ comprises -hydrogen, -alkyl, -aryl,-arylene-alkyl, -alkylene-aryl, or -alkylene-arylene-alkyl. In anotherembodiment, X comprises —CON(R₉)—, wherein R₉ comprises -hydrogen.

Ar₁ comprises an aryl, heteroaryl, fused cycloalkylaryl, fusedcycloalkylheteroaryl, fused heterocyclylaryl, or fusedheterocyclylheteroaryl group optionally substituted 1 to 7 times. Inanother embodiment, Ar₁ comprises a mono- or bicyclic aryl or heteroarylgroup optionally substituted 1 to 7 times. In another embodiment, Ar₁comprises a phenyl group having 1 to 5 substituents. In variousembodiments of Ar₁, the substituents of Ar₁ may independently comprise:

-   -   a) -fluoro;    -   b) -chloro;    -   c) -bromo;    -   d) -iodo;    -   e) -cyano;    -   f) -nitro;    -   g) -perfluoroalkyl;    -   h) -D-R₁₂;    -   i) -alkyl;    -   j) -aryl;    -   k) -heteroaryl;    -   l) -heterocyclyl;    -   m) -cycloalkyl;    -   n) -alkylene-aryl;    -   o) -alkylene-arylene-aryl;    -   p) -alkylene-arylene-alkyl;    -   q) -arylene-alkyl;    -   r) -arylene-arylene-alkyl;    -   s) -D-alkyl;    -   t) -D-aryl;    -   u) -D-alkylene-aryl;    -   v) -D-arylene-alkyl;    -   w) -D-alkylene-arylene-aryl;    -   x) -D-arylene-arylene-aryl;    -   y) -D-alkylene-arylene-alkyl;    -   z) -alkylene-D-alkylene-aryl;    -   aa) -arylene-D-alkyl;    -   bb) -alkylene-D-aryl;    -   cc) -alkylene-D-heteroaryl;    -   dd) -alkylene-D-cycloalkyl;    -   ee) -alkylene-D-heterocyclyl;    -   ff) -alkylene-D-arylene-alkyl;    -   gg) -alkylene-D-alkylene-arylene-alkyl;    -   hh) -alkylene-D-alkyl;    -   ii) -alkylene-D-R₁₃;    -   jj) -arylene-D-R₁₃;    -   jj) -arylene-T-R₁₇;    -   kk) -T-alkylene-arylene-heteroaryl;    -   ll) -T-alkylene-heterocyclyl;    -   mm) -T-alkylene-heteroaryl;    -   nn) -T-heteroaryl;    -   oo) -T-fused heterocyclylaryl;    -   pp) -T-fused cycloalkylaryl;    -   qq) -T-fused arylcycloalkyl;    -   rr) -T-fused fused heterocyclylaryl;    -   ss) -T-fused fused arylheterocyclyl;    -   tt) -T-fused fused cycloalkylheteroaryl;    -   uu) -T-fused fused heteroarylcycloalkyl;    -   vv) -T-fused heterocyclylheteroaryl;    -   ww) -T-fused heteroarylheterocyclyl; or    -   xx) -hydrogen;        wherein T comprises a direct bond, —CH₂—, —O—, —N(R₁₈)—, —C(O)—,        —CON(R₁₈)—, —N(R₁₈)C(O)—, —N(R₁₈)CON(R₁₉)—, —N(R₁₈)C(O)O—,        —OC(O)N(R₁₈)—, —N(R₁₈)SO₂—, —SO₂N(R₁₈)—, —C(O)—O—, —O—C(O)—,        —S—, —S(O)—, —S(O₂)—, —N(R₁₈)SO₂N(R₁₉)—,        and wherein R₁₇, R₁₈, R₁₉ and R₂₀, independently comprise:        -hydrogen, -alkyl, -aryl, -arylene-alkyl, -alkylene-aryl, or        -alkylene-arylene-alkyl. In another embodiment, Ar₁ comprises a        mono-substituted phenyl group wherein the substituent comprises:        -aryl, -arylene-alkyl, -D-aryl, -D-alkylene-arylene-alkyl, or        -arylene-D-alkyl; wherein D comprises —O—, —N(R₁₄)—, —CON(R₁₄)—,        or —N(R₁₄)C(O)—, and wherein R₁₄ comprises: -hydrogen; -alkyl;        or -aryl.

In another embodiment, Ar₁ comprises:2′-(4-tert-butyl-phenoxy)-biphenyl-4-yl,2′-(4-trifluoromethyl-phenoxy)-biphenyl-4-yl, 2′-phenoxy-biphenyl-4-yl,2′-trifluoromethyl-biphenyl-4-yl, 3′,4′-dichloro-biphenyl-4-yl,3′,4′-difluoro-biphenyl-4-yl, 3′,5′-bis-trifluoromethyl-biphenyl-4-yl,3′,5′-difluoro-biphenyl-4-yl,3′-chloro-4′-fluoro-6-methoxy-biphenyl-3-yl,3′-chloro-4′-fluoro-biphenyl-2-yl, 3′-chloro-4′-fluoro-biphenyl-3-yl,3′-chloro-4′-fluoro-biphenyl-4-yl, 3′-chloro-biphenyl-4-yl,3′-nitro-biphenyl-4-yl, 3′-trifluoromethoxy-biphenyl-4-yl,3′-trifluoromethyl-biphenyl-4-yl, 4′-benzyloxy-3′-fluoro-biphenyl-4-yl,4-benzyloxy-phenyl, 4′-chloro-biphenyl-4-yl, 4′-fluoro-biphenyl-4-yl,4′-methanesulfonyl-biphenyl-4-yl, 4-naphthalen-2-yl-phenyl,4′-nitro-biphenyl-4-yl, 4′-phenoxy-biphenyl-4-yl,4-pyridin-3-yl-phenyl4′-tert-butyl-biphenyl-4-yl,4′-trifluoromethyl-biphenyl-4-yl, 6-methoxy-4′-nitro-biphenyl-3-yl,biphenyl, biphenyl-4-yl, chlorofluorophenoxy-phenyl, or(cyano-phenoxy)-phenyl.

In another embodiment, Ar₁ comprises:[2-(4-chloro-phenyl)-ethoxy]-phenyl, (4-nitro-phenoxy)-phenyl,(3-phenyl-propylamino)-phenyl, 4-methoxy-4′-nitro-biphenyl-3-yl,(4′-methanesulfonyl-4-methoxy-biphenyl-3-yl), or(4′-methanesulfonyl-4-hydroxy-biphenyl-3-yl).

In another embodiment, Ar₁ comprises an unsubstituted biphenyl group.

In yet another embodiment, Ar₁ comprises a biphenyl group substitutedwith at least one of the following groups fluoro, chloro,trifluoroalkyl, trifluoroalkoxy, nitro, benzyloxy, phenoxy, andalkylsulfonyl.

Ar₂ comprises an aryl or heteroaryl group optionally substituted 1 to 7times. In one embodiment, Ar₂ comprises a phenyl, naphthyl, pyridyl,isoquinolyl, pyrimidyl or quinazolyl group optionally substituted 1 to 7times. In another embodiment, Ar₂ comprises a substituted phenyl,2-naphthyl, 2-pyridyl, 3-isoquinolyl, 2-pyrimidyl or 2-quinazolyl grouphaving 1 to 5 substituents. In various embodiments of Ar₂, thesubstituents of Ar₂ may independently comprise:

-   -   a) -fluoro;    -   b) -chloro;    -   c) -bromo;    -   d) -iodo;    -   e) -cyano;    -   f) -nitro;    -   g) -perfluoroalkyl;    -   h) -T-R₁₇;    -   i) -alkyl;    -   j) -aryl;    -   k) -heteroaryl;    -   l) -heterocyclyl;    -   m) -cycloalkyl;    -   n) -alkylene-aryl;    -   o) -alkylene-arylene-aryl;    -   p) -alkylene-arylene-alkyl;    -   q) -arylene-alkyl;    -   r) -arylene-arylene-alkyl;    -   s) -T-alkyl;    -   t) -T-aryl;    -   u) -T-alkylene-aryl;    -   v) -T-arylene-alkyl;    -   w) -T-alkylene-arylene-aryl;    -   x) -T-arylene-arylene-aryl;    -   y) -T-alkylene-arylene-alkyl;    -   z) -alkylene-T-alkylene-aryl;    -   aa) -arylene-T-alkyl;    -   bb) -alkylene-T-aryl;    -   cc) -alkylene-T-heteroaryl;    -   dd) -alkylene-T-cycloalkyl;    -   ee) -alkylene-T-heterocyclyl;    -   ff) -alkylene-T-arylene-alkyl;    -   gg) -alkylene-T-alkylene-arylene-alkyl; or    -   hh) -alkylene-T-alkyl;    -   ii) -alkylene-T-R₁₇;    -   jj) -arylene-T-R₁₇; or    -   kk) -hydrogen;        wherein T comprises —CH₂—, —O—, —N(R₁₈)—, —C(O)—, —CON(R₁₈)—,        —N(R₁₈)C(O)—, —N(R₁₈)CON(R₁₉)—, —N(R₁₈₁)C(O)O—, —OC(O)N(R₁₈)—,        —N(R₁₈)SO₂—, —SO₂N(R₁₈)—, —C(O)—O—, —O—C(O)—, —S—, —S(O)—,        —S(O₂)—, —N(R₁₈)SO₂N(R₁₉)—,        and wherein R₁₇, R₁₈, R₁₉ and R₂₀, independently comprise:        -hydrogen, -alkyl, -aryl, -arylene-alkyl, -alkylene-aryl, or        -alkylene-arylene-alkyl. In another embodiment, Ar₂ comprises a        substituted phenyl, 2-naphthyl, 2-pyridyl, 3-isoquinolyl,        2-pyrimidyl or 2-quinazolyl group having 1 to 5 substituents        independently comprising:    -   a) -fluoro;    -   b) -chloro;    -   c) -bromo;    -   d) -iodo;    -   e) -cyano;    -   f) -nitro;    -   g) -perfluoroalkyl;    -   h) -T-R₁₇;    -   i) -alkyl;    -   j) -aryl;    -   k) -arylene-alkyl;    -   l) -T-alkyl;    -   m) -T-alkylene-aryl;    -   n) -T-alkylene-arylene-aryl;    -   o) -T-alkylene-arylene-alkyl; or    -   p) -arylene-T-alkyl;        wherein T comprises —CH₂—, —O—, —N(R₁₈)—, —CON(R₁₈)—, or        —N(R₁₈)C(O)—; wherein R₁₇, and R₁₈, independently comprise:        -hydrogen, -alkyl, or -aryl.

In another embodiment, Ar₂ comprises:3′-chloro-4′-fluoro-4-hydroxy-biphenyl,2-hydroxy-5-[2-(4′-trifluoromethyl-biphenyl-3-yl)-acetylamino]-phenyl,2-hydroxy-5-pyridin-3-yl-phenyl, 3′,5′-difluoro-4-hydroxy-biphenyl,3′-chloro-4′-fluoro-4-hydroxy-biphenyl, 3′-fluoro-4-hydroxy-biphenyl,3′-trifluoromethyl-biphenyl-4-yl,4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl,4′-amino-4-hydroxy-biphenyl, 4′-fluoro-4-hydroxy-biphenyl,4-hydroxy-2′-trifluoromethyl-biphenyl,4-hydroxy-3′,5′-bis-trifluoromethyl-biphenyl,4-hydroxy-3′-nitro-biphenyl, 4-hydroxy-4′-trifluoromethoxy-biphenyl,4-Hydroxy-4′-trifluoromethyl-biphenyl, 4-hydroxy-biphenyl,5-benzo[1,3]dioxol-5-yl-2-hydroxy-phenyl, 5-bromo-2-hydroxy-phenyl,5-chloro-4-hydroxy-4′-trifluoromethyl-biphenyl,5-fluoro-4-hydroxy-4′-trifluoromethyl-biphenyl, or6-benzyloxy-4-hydroxy-4′-trifluoromethyl-biphenyl.

In another embodiment, Ar₂ comprises3′-chloro-4′-fluoro-4-hydroxy-biphenyl, or4-Hydroxy-4′-trifluoromethyl-biphenyl.

In another embodiment, Ar₂ comprises:[2-(3,4-bis-benzyloxy-benzyloxy)-benzyloxy]-5-bromo-phenyl,2-(4-tert-butyl-benzyloxy)-5-chlorophenyl,3-bromo-5-chloro-2,6-dimethoxy-phenyl,4-(4-tert-butyl-benzyloxy)-4′-trifluoromethyl-biphenyl,4-acetoxy-2-phneyl-4′-trifluoromethyl-biphenyl,4-acetoxy-4′-trifluoromethyl-biphenyl,4-amino-4′-trifluoromethyl-biphenyl,4-butoxy-3′-chloro-4′-fluoro-biphenyl,4-methanesulfonylamino-4′-trifluoromethyl-biphenyl,4-methoxy-4′-trifluoromethyl-biphenyl,5-bromo-2-(4-[1,2,4]triazol-1-yl-benzyloxy)-phenyl,5-bromo-2-(4-tert-butyl-benzyloxy)-phenyl,5-bromo-2-cyclohexyloxy-phenyl, 5-bromo-2-heptyloxy-phenyl,5-chloro-2,4-dimethoxy-4′-trifluoromethyl-biphenyl,5-chloro-2-heptyloxy-phenyl.

In another embodiment, Ar₂ comprises:5-bromo-2-(3-pyridin-4-yl-propoxy)-phenyl,5-bromo-2-[2-(2-oxo-pyrrolidin-1-yl)-ethoxy]-phenyl,5-bromo-2-(2-morpholin-4-yl-ethoxy)-phenyl,5-bromo-2-(4,4,4-trifluoro-butoxy)-phneyl, or5-bromo-2-(2-piperidin-1-yl-ethoxy)-phenyl.

In another embodiment, Ar₂ comprises 3-hydroxy-naphthalene.

In another embodiment, Ar₂ comprises a phenyl or biphenyl groupcontaining a hydroxy, alkyloxy, or acetoxy group ortho to the Ar₂group's point of attachment to X.

In yet another embodiment, Ar₂ comprises a phenyl or biphenyl groupcontaining a hydroxy, alkyloxy, or acetoxy group ortho to the Ar₂group's point of attachment to X and further substituted with at leastone of the following groups fluoro, chloro, trifluoroalkyl,trifluoroalkoxy, nitro, benzyloxy, phenoxy, phenyl, and alkylsulfonyl.

The alkyl, aryl, heteroaryl, alkylene, and arylene groups in Ar₁, Ar₂,G, R₁—R₂₁, may be optionally substituted 1 to 4 times with a substituentgroup, wherein said substituent group(s) or the term substituted refersto groups comprising:

-   -   a) -hydrogen;    -   b) -fluoro;    -   c) -chloro;    -   d) -bromo;    -   e) -iodo;    -   f) -cyano;    -   g) -nitro;    -   h) -perfluoroalkyl;    -   i) -Q-R₂₂;    -   j) -Q-alkyl;    -   k) -Q-aryl;    -   l) -Q-alkylene-aryl;    -   m) -Q-alkylene-NR₂₃R₂₄; or    -   n) -Q-alkyl-W—R₂₅;        wherein Q and W independently comprise: —CH₂—, —O—, —N(R₂₆)—,        —C(O)—, —CON(R₂₆)—, —N(R₂₆)C(O)—, —N(R₂₆)CON(R₂₇)—,        —N(R₂₆)C(O)O—, —OC(O)N(R₂₆)—, —N(R₂₆)SO₂—, —SO₂N(R₂₆)—,        —C(O)—O—, —O—C(O)—, or —N(R₂₆)SO₂N(R₂₇)—, wherein R₂₂, R₂₃, R₂₄,        R₂₅, R₂₆ and R₂₇, independently comprise: -hydrogen, -alkyl,        -aryl, -arylene-alkyl, -alkylene-aryl, or        -alkylene-arylene-alkyl.

Also included within the scope of the invention are the individualenantiomers of the compounds represented by Formula (I) above as well asany wholly or partially racemic mixtures thereof. The present inventionalso covers the individual enantiomers of the compounds represented byformula above as mixtures with diastereoisomers thereof in which one ormore stereocenters are inverted.

Compounds of the present invention are listed in Table 1. TABLE 1 Ex.Structure Chemical Name 1

3-Biphenyl-4-yl-(2S)-[(3′-chloro-4′-fluoro- 4-hydroxy-biphenyl-3-carbonyl)- amino]-propionic acid methyl ester 2

4-Hydroxy-4′-trifluoromethyl-biphenyl-3- carboxylic acidbiphenyl-4-yl-1(S)- formyl-ethyl)-amide; compound with methoxymethane 3

2-(S)-[(4-Hydroxy-4′-trifluoromethyl- biphenyl-3-carbonyl)-amino]-3-(4′-trifluoromethyl-biphenyl-4-yl)propionic acid methyl ester 4

3-Biphenyl-4-yl-(2S)-[(4-hydroxy-3′- nitro-biphenyl-3-carbonyl)-amino]-propionic acid methyl ester 5

3-Biphenyl-4-yl-2-(S)-[(4-hydroxy-4′-trifluoromethoxy-biphenyl-3-carbonyl)- amino]-propionic acid methylester 6

3-Biphenyl-4-yl-2-(S)-[(4′-fluoro-4-hydroxy-biphenyl-3-carbonyl)-amino]- propionic acid methyl ester 7

3-Biphenyl-4-yl-2-(2S)-[(3′-fluoro-4-hydroxy-biphenyl-3-carbonyl)-amino]- propionic acid methyl ester 8

3-Biphenyl-4-yl-2-(2S)-[(4-hydroxy-3′,5′-bis-trifluoromethyl-biphenyl-3-carbonyl)- amino]-propionic acid methylester 9

3-Biphenyl-4-yl-2-(2S)-[(3′,5′-difluoro-4-hydroxy-biphenyl-3-carbonyl)-amino]- propionic acid methyl ester 10

2-(2S)-[(3′-Chloro-4′-fluoro-4-hydroxy-biphenyl-3-carbonyl)-amino]-3-(4′-trifluoromethyl-biphenyl-4-yl)-propionic acid ester 11

2-(2S)-(5-Benzo[1,3]dioxol-5-yl-2-hydroxy-benzoylamino)-3-biphenyl-4-yl- propionic acid methyl ester 12

3-(3′-Chloro-4′-fluoro-biphenyl-4-yl)-2-(2S)-[(4-hydroxy-4′-trifluoromethyl-biphenyl-3-carbonyl)-amino]-propionic acid methyl ester 13

3-(3′5′-Bis-trifluoromethyl-biphenyl-4-yl)-2-(2S)-[(3′-chloro-4′-fluoro-4-hydroxy-biphenyl-3-carbonyl)-amino]-propionic acid methyl ester 14

3-(3′,5′-Bis-trifluoromethyl-biphenyl-4-yl)-2-(2S)-[(3′chloro-4′-fluoro-4-hydroxy-biphenyl-3-carbonyl)amino]-propionic acid methyl ester 15

2-(2S)-[(3′-Chloro-4′-fluoro-4-hydroxybiphenyl-3-carbonyl)-amino]-3-(3′-trifluoromethyl-biphenyl-4-yl)-propionic acid methyl ester 16

2-(2S)-[(4-Hydroxy-4′-trifluoromethyl-biphenyl-3-carbonyl)-amino]-3-(3′-trifluoromethoxy-biphenyl-4-yl)-propionic acid methyl ester 17

2-(2S)-[(4-Hydroxy-3′-trifluoromethyl-biphenyl-3-carbonyl)-amino]-3-(3′-trifluoromethyl-biphenyl-4-yl)-propionic acid methyl ester 18

3-Biphenyl-4-yl-2-(S)-[(4-hydroxy- biphenyl-3-carbonyl)-amino]-propionicacid methyl ester 19

2-(S)-[(3′-Chloro-4′-fluoro-4-hydroxy-biphenyl-3-carbonyl)-amino]-3-(3′-trifluoromethoxy-biphenyl-4-yl)-propionic acid methyl ester 20

2-(S)-[(4-Hydroxy-2′-trifluoromethyl- biphenyl-3-carbonyl)-amino]-3-(2′-trifluoromethyl-biphenyl-4-yl)-propionic acid methyl ester 21

3-(3′-Chloro-4′-fluoro-biphenyl-4-yl)-2-(S)-[(3′-chloro-4′-fluoro-4-hydroxy-biphenyl-3-carbonyl)-amino]-propionic acid methyl ester 22

2-(S)-[(4-Hydroxy-3′-nitro-biphenyl-3-carbonyl)-amino]-3-(3′-nitro-biphenyl-4- yl)-propionic acid methyl ester23

2-(S)-[(4-Hydroxy-3′-trifluoromethyl- biphenyl-3-carbonyl)-amino]-3-(4′-trifluoromethyl-biphenyl-4-yl)-propionic acid methyl ester 24

3-(3′-Chloro-4′-fluoro-biphenyl-4-yl)-2-(S)-[(4-hydroxy-3′-trifluoromethyl-biphenyl-3-carbonyl)-amino]-propionic acid methyl ester 25

3-Biphenyl-4-yl-2-(S)-[(4-hydroxy-2′-trifluoromethyl-biphenyl-3-carbonyl)- aminol]propionic acid methyl ester26

3-(3′,5′-Bis-trifluoromethyl-biphenyl-4-yl)-2-(S)-[(4-hydroxy-3′-trifluoromethyl-biphenyl-3-carbonyl)-amino]-propionic acid methyl ester 27

2-(S)-[(4-Hydroxy-3′-trifluoromethyl- biphenyl-3-carbonyl)-amino]-3-(2′-trifluoromethyl-biphenyl-4-yl)-propionic acid methyl ester 28

2-(2S)-[(4-Hydroxy-4-trifluoromethyl-biphenyl-3-carbonyl)-amino]-3-(4′-nitro- biphenyl-4-yl)-propionic acidmethyl 29

3-(3′,4′-Difluoro-biphenyl-4-yl)-2-(S)(2-hydroxy-5-pyridin-3-yl-benzoylamino)- propionic acid methyl ester 30

2-(S)-[4′-Amino-hydroxy-biphenyl-3- carbonyl)-amino]-3-biphenyl-4yl-propionic acid methyl ester 31

3-Biphenyl-4-yl-2-(2S)-{2-hydroxy-5-[2-(4′-trifluoromethyl-biphenyl-3-yl)- acetylamino]-benzoylamino]propionicacid methyl ester 32

3-Biphenyl-4-yl-2-(S)-[(3′-chloro-4′-fluoro-4-hydroxy-biphenyl-3-carbonyl)- amino}-propionic acid methylester 33

3-Biphenyl-4-yl-2-(S)-[(3′-chloro-4′-fluoro-4-hydroxy-biphenyl-3-carbonyl)- amino]-propionic acid 34

2-(S)-(5-Chloro-2-hydroxy- benzoylamino)-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid methyl ester 35

2-(S)-(5-Chloro-2-hydroxy- benzoylamino)-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid 36

2-(S)-(5-Bromo-2-hydroxy- benzoylamino)-3-(4′-phenoxy-biphenyl-4-yl)-propionic acid methyl ester 37

2-(S)-(5-Bromo-2-hydroxy- benzoylamino)-3-(4′-phenoxy-biphenyl-4-yl)-propionic acid 38

5-Chloro-4-hydroxy-4′-trifluoromethyl- biphenyl-3-carboxylic acid[2-(3′-chloro- 4′-fluoro-biphenyl-3-yl)-1(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide 39

5-Chloro-4-hydroxy-4′-trifluoromethyl- biphenyl-3-carboxylic acid[2-[4-(3- chloro-4-fluorophenoxy)-phenyl]-1(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide 40

3-(4′-Chloro-biphenyl-4-yl)-2-(R)-[(4-methoxy-4′-trifluoromethyl-biphenyl-3- carbonyl)-amino]-propionic acidmethyl ester 41

3-(4′-Chloro-biphenyl-4-yl)-2-(R)-[(4-methoxy-4′-trifluoromethyl-biphenyl-3- carbonyl)-amino]-propionic acid42

4-Hydroxy-4′-trifluoromethyl-biphenyl-3- carboxylic acid[2-(3′-chloro-biphenyl-4-yl)- 1(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide 43

4-Hydroxy-4′-trifluoromethyl-biphenyl-3- carboxylic acid[2-(4′-chloro-biphenyl-4- yl)-1(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide 44

4-Hydroxy-4′-trifluoromethyl-biphenyl-3- carboxylic acid[2-(3′-chloro-4′-fluoro- biphenyl-4-yl)-1(R)-(3-trifluoromethyl[1,2,4]oxadiazol-5-yl)- ethyl]-amide 45

4-Hydroxy-4′-trifluoromethyl-biphenyl-3- carboxylic acid[1(R)-(3-tert-butyl- [1,2,4]oxadiazol-5-yl)-2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-ethyl]-amide 46

5-(3′-Chloro-4′-fluoro-biphenyl-4-yl)-4-[(4-hydroxy-4′-trifluoromethyl-biphenyl- 3(R)-carbonyl)amino]-pent-2-enoic acid ethyl ester 47

4-Hydroxy-4′-trifluoromethyl-biphenyl-3- carboxylic acid[2-(3′-chloro-4′-fluoro-6- methoxy-biphenyl-3-yl)-ethyl]-amide 48

2-(S)-[(4-Amino-4′-trifluoromethyl- biphenyl-3-carbonyl)-amino]-3-(3′-chloro-4′-fluoro-biphenyl-4-yl)-propionic acid methyl ester 49

3-(3′-Chloro-4′-fluoro-biphenyl-4-yl)-2- (S)-[(4-methanesulfonylamino-4′- trifluoromethyl-biphenyl-3-carbonyl)- amino]propionic acidmethyl ester 50

3′-Chloro-4′-fluoro-4-hydroxy-biphenyl- 3-carboxylic acid(2-biphenyl-4-yl-1(S)- methylcarbamoyl-ethyl)-amide 51

3′-Chloro-4′-fluoro-4-hydroxy-biphenyl- 3-carboxylic acid{2-biphenyl-4-yl-1-(S)- [2-(4-chloro-phenyl)-ethylcarbamoyl]-ethyl}-amide 52

3′-Chloro-4′-fluoro-4-hydroxy-biphenyl- 3-carboxylic acid(1-(S)-allylcarbamoyl- 2-biphenyl-4-yl-ethyl)-amide 53

2-(S)-{3-Biphenyl-4-yl-2-(S)-[(3′-chloro-4′-fluoro-4-hydroxy-biphenyl-3- carbonyl)amino]propionylamino}-3-methyl-butyricacid 54

3-(S)-{3-Biphenyl-4-yl-2-[(3′-chloro-4′-fluoro-4-hydroxy-biphenyl-3-carbonyl)- amino]propionylamino}-propionicacid 55

3′-Chloro-4′-fluoro-4-hydroxy-biphenyl- 3-carboxylic acid[2-biphenyl-4-yl-1-(S)- (2-methoxy-ethylcarbamoyl)-ethyl]- amide 56

2-(S)-[2-(S)-[(3′-Chloro-4′-fluoro-4-hydroxy-biphenyl-3-carbonyl)-amino]-3-(3′-trifluoromethyl-biphenyl-4-yl)- propionylamino]-hexanoic acid 57

1-[2-(S)-[(3′-Chloro-4′-fluoro-4-hydroxy-biphenyl-3-carbonyl)-amino]-3-(3′-trifluoromethyl-biphenyl-4-yl)-propionyl]- pyrrolidine-2-(S)-carboxylicacid 58

2-(S)-[2-(S)-[(3′-Chloro-4′-fluoro-4-hydroxy-biphenyl-3-carbonyl)-amino]-3-(3′-trifluoromethyl-biphenyl-4-yl)- propionylamino]-4-methylpentanoicacid 59

{[2-(S)-[(3′-Chloro-4′-fluoro-4-hydroxybiphenyl-3-carbonyl)-amino]-3-(3′-trifluoromethyl-biphenyl-4-yl)-propionyl]- methyl-amino}-acetic acid 60

[2-(S)-[(3′-Chloro-4′-fluoro-4-hydroxy-biphenyl-3-carbonyl)-amino]-3-(3′- trifluoromethyl-biphenyl-4-yl)-propionylamino]-2-(S)-phenyl-acetic acid 61

2-(S)-[2-(S)-[(3′-Chloro-4′-fluoro-4-hydroxy-biphenyl-3-carbonyl)-amino]-3-(3′-trifluoromethyl-biphenyl-4-yl)-propionylamino]-3-(4-hydroxy-phenyl)- propionic acid 62

2-(S)-[2-(S)-[(3′-Chloro-4′-fluoro-4-hydroxy-biphenyl-3-carbonyl)-amino]-3-(3′-trifluoromethyl-biphenyl-4-yl)- propionylamino]-propionic acid 63

2-(S)-[2-(S)-[(3′-Chloro-4′-fluoro-4-hydroxy-biphenyl-3-carbonyl)-amino]-3-(3′-trifluoromethyl-biphenyl-4-yl)- propionylamino]-3-methyl-butyricacid 64

2-(S)-[2-(S)-](3′-Chloro-4′-fluoro-4-hydroxy-biphenyl-3-carbonyl)-amino]-3-(3′trifluoromethyl-biphenyl-4-yl)- propionylamino]-pentanedioic acid 65

2-(S)-[2-(S)-[(3′-Chloro-4′-fluoro-4-hydroxy-biphenyl-3-carbonyl)-amino]-3-(3′-trifluoromethyl-biphenyl-4-yl)- propionylamino]-succinic acid 66

4-Methoxy-4′-trifluoromethyl-biphenyl-3- carboxylic acid[2-(R)-(4-methyl- piperazin-1-yl)-2-oxo-1 -(4′-trifluoromethyl-biphenyl-4-ylmethyl)- ethyl]-amide 67

4-Hydroxy-4′-trifluoromethyl-biphenyl-3- carboxylic acid[1-(3′-chloro-4′-fluoro- biphenyl-4-ylmethyl)-2-(S)-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-amide 68

4-Hydroxy-4′-trifluoromethyl-biphenyl-3- carboxylic acid{2-(3′-chloro-4′-fluoro- biphenyl-4-yl)-1-(R)-[(2-dimethylamino-ethyl)-methyl-carbamoyl]-ethyl}-amide 69

4-Hydroxy-4′-trifluoromethyl-biphenyl-3- carboxylic acid[1-(R)-(3′-chloro-4′- fluoro-biphenyl-4-ylmethyl)-2-oxo- propyl]-amide70

4-Hydroxy-4′-trifluoromethyl-biphenyl-3- carboxylic acid[2-(3′-chloro-4′-fluoro- biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyI]-amide 71

4-Hydroxy-4′-methanesulfonyl-biphenyl- 3-carboxylic acid[2-(4′-methanesulfonyl-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]- amide 72

4-Hydroxy-3′,5′-bis-trifluoromethyl- biphenyl-3-carboxylic acid [2-(4′-methanesulfonyl-biphenyl-4-yl)-1-(R)-(-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]- amide 73

3′,4-Difluoro-4-hydroxy-biphenyl-3- carboxylic acid [2-(3′,4′-difluoro-biphenyl-4-yl)-1-(R)-(3-methyl- [1,2,4]oxadiazol-5-yl)-ethyl]-amide 74

4-Hydroxy-4′-trifluoromethyl-biphenyl-3- carboxylic acid[1-(R)-(3-methyl- [1,2,4]oxadiazol-5-yl)-2-(4′-trifluoromethyl-biphenyl-4-yl)-ethyl]- amide 75

4-Hydroxy-3′,5′-bis-trifluoromethyl- biphenyl-3-carboxylic acid[2-(3′-chloro- 4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide 76

Acetic acid 3-[2-(3′-chloro-4′-fluoro- biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethylcarbamoyl]- 4′-trifluoromethyl-biphenyl-4-ylester 77

4-Hydroxy-4′-trifluoromethyl-biphenyl-3- carboxylic acid[2-(4′-benzyloxy-3′- fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide 78

4-Hydroxy-4′-trifluoromethyl-biphenyl-3- carboxylic acid[2-(4′-methanesulfonyl- biphenyl-4-yl)-1-(R)(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide 79

4-Hydroxy-4′-nitro-biphenyl-3-carboxylic acid[2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl) -ethyl]-amide 80

6-Benzyloxy-4-hydroxy-4′- trifluoromethyl-biphenyl-3-carboxylic acid[2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl) -ethyl]-amide 81

5-Chloro-4-hydroxy-4′-trifluoromethyl- biphenyl-3-carboxylic acid[2-(3′-chloro- 4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide 82

Acetic acid 5′-[2-(3′-chloro-4-fluoro- biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl) ethylcarbamoyl]-4-trifluoromethyl[1,1′;3′,1″]terphenyl-4′-yl ester 83

4-Hydroxy-4′-trifluoromethyl-biphenyl-3- carboxylic acid[2-(4-benzyloxy-phenyl)- 1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide 84

4-Hydroxy-4′-trifluoromethyl-biphenyl-3- carboxylic acid[2-(4′-fluoro-biphenyl-4- yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide 85

5-Fluoro-4-hydroxy-4′-trifluoromethyl- biphenyl-3-carboxylic acid[2-(3′-chloro- 4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide 86

4-Hydroxy-4′-trifluoromethyl-biphenyl-3- carboxylic acid[2-[4-(3-chloro-4-fluoro- phenoxy)-phenyl]-1-(R)-(3-methyl1,2,4]oxadiazol-5-yl)-ethyl]-amide 87

4-Hydroxy-4′-trifluoromethyl-biphenyl-3- carboxylic acid[2-(3′-chloro-4′-fluoro- biphenyl-3-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide 88

4-Hydroxy-4′-trifluoromethyl-biphenyl-3- carboxylic acid[2-(3′-chloro-4′-fluoro- biphenyl-2-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide 89

5-Bromo-N-[2-(3′-chloro-4′-fluoro- biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-2-hydroxy- benzamide 90

4-Hydroxy-3′,5′-bis-trifluoromethyl- biphenyl-3-carboxylic acid[2-biphenyl- 4-yl-1-(R)-(3-methyl-[1,2,4]oxadiazol-5- yl)-ethyl]-amide91

Acetic acid 3-[2-(6-methoxy-4′-nitro- biphenyl-3-yl)-ethylcarbamoyl]-naphthalen-2-yl ester 92

3-Biphenyl-4-yl-2-(S)-[(3-hydroxy- naphthalene-2-carbonyl)-amino]-propionic acid methyl ester 93

3-(3′-Chloro-4′-fluoro-biphenyl-4-yl)-2- (S)-[(3-hydroxy-naphthalene-2-carbonyl)-amino]-propionic acid methyl ester 94

3-(4′-Fluoro-biphenyl-4-yl)-2-(S)-[(3- hydroxy-naphthalene-2-carbonyl)-amino]-propionic acid methyl ester 95

3-(3′,4′-Difluoro-biphenyl-4-yl)-2-(S)-[(3-hydroxy-naphthalene-2-carbonyl)- amino]-propionic acid methyl ester 96

3-(4′-Chloro-biphenyl-4-yl)-2-(S)-[(3- hydroxy-naphthalene-2-carbonyl)-amino]-propionic acid methyl ester 97

2-(S)-[(3-Hydroxy-naphthalene-2-carbonyl)-amino]-3-(4′-trifluoromethoxy- biphenyl-4-yl)-propionic acidmethyl ester 98

2-(S)-[(3-Hydroxy-naphthalene-2- carbonyl)-amino]-3-(4′-trifluoromethyl-biphenyl-4-yl)-propionic acid methyl ester 99

3-(3′,5′-Bis-trifluoromethyl-biphenyl-4-yl)-2-(S)-[(3-hydroxy-naphthalene-2- carbonyl)-amino]-propionic acidmethyl ester 100

3-(3′,5′-Difluoro-biphenyl-4-yl)-2-(S)-[(3-hydroxy-naphthalene-2-carbonyl)- amino]-propionic acid methyl ester 101

2-(S)-[(3-Hydroxy-naphthalene-2-carbonyl)-amino]-3-[1.1′;4′,1″terphenyl- 4-yl-propionic acid methylester 102

3-(2′-Fluoro-[1,1′;4′,1″]terphenyl-4″-yl)-2-(S)-[(3-hydroxy-naphthalene-2- carbonyl)-amino]-propionic acid methylester 103

3-(4′-tert-Butyl-biphenyl-4-yl)-2-[(3-hydroxy-napthalene-2-(S)-carbonyl)-amino]-propionic acid methyl ester104

2-(S)-[(3-Hydroxy-naphthalene-2- carbonyl)-amino]-3-(4-naphthalen-2-yl-phenyl)-propionic acid methyl ester 105

3-{4-[2-(4-Chloro-phenyl)-ethoxy]-phenyl}-2-(S)-[(3-hydroxy-naphthalene- 2-carbonyl)-amino]-propionic acidmethyl ester 106

2-(S)-[(3-Hydroxy-naphthalene-2- carbonyl)-amino]-3-(4-naphthalen-2-ylphenyl)-propionic acid methyl ester 107

2-(S)-[(3-Hydroxy-naphthalene-2-carbonyl)-amino]-3-[4-(4-nitro-phenoxy)- phenyl]propionic acid methylester 108

2-(S)-[(3-Hydroxy-naphthalene-2- carbonyl)-amino]-3-[4-(3-phenyl-propylamino)-phenyl]-propionic acid methyl ester 109

(2-(S)-[(3-Hydroxy-naphthalene-2-carbonyl)-amino]-3-(4′-trifluoromethyl-biphenyl-4-yl)-propionylamino]-acetic acid methyl ester 110

3-Hydroxy-naphthalene-2-carboxylic acid[2-(4-methoxy-4′-nitro-biphenyl-3- yl)-ethyl]-amide 111

3-Hydroxy-naphthalene-2-carboxylic acid[2-(6-methoxy-4′-nitro-biphenyl-3- yl)-ethyl]-amide 112

3-Hydroxy-naphthalene-2-carboxylic acid[2-(4′-methanesulfonyl-4-methoxy- biphenyl-3-yl)-ethyl]-amide 113

3-Hydroxy-naphthalene-2-carboxylic acid[2-(4-hydroxy-4′-methanesulfonyl- biphenyl-3-yl)-ethyl]-amide 114

(3-{2-[(3-Hydroxy-naphthalene-2- carbonyl)-amino]-ethyl}-4′-methanesulfonyl-biphenyl-4-yloxy)- acetic acid ethyl ester 115

3-Hydroxy-naphthalene-2-carboxylic acid[2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5- yl)-ethyl]-amide 116

2-(S)-[5-Bromo-2-(2-morpholin-4-yl- ethoxy)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid methyl ester 117

2-(S)-[5-Bromo-2-(3-pyridin-4-yl- propoxy)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid methyl ester 118

2-(S)-{5-Bromo-2-[2-(2-oxo-pyrrolidin-1-yl)-ethoxy]-benzoylamino}-3-(2′- phenoxy-biphenyl-4-yl)-propionic acidmethyl ester 119

2-(S)-[5-Bromo-2-(4,4,4-trifluoro- butoxy)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid 120

2-(S)-[5-Bromo-2-(2-pyrrolidin-1-yl-ethoxy)-benzoylamino]-3-(2′-phenoxy- biphenyl-4-yl)-propionic acidmethyl ester 121

2-S)-[5-Bromo-2-(2-piperidin-1-yl- ethoxy)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid methyl ester 122

2-(S)-[(4-Butoxy-3′-chloro-4′-fluoro- biphenyl-3-carbonyl)-amino]-3-(3′-trifluoromethyl-biphenyl-4-yl)-propionic acid 123

2-(S)-(5-Chloro-2-heptyloxy- benzoylamino)-3-(4′-trifluoromethoxy-biphenyl-4-yl)-propionic acid 124

2-(S)-(5-Bromo-2-heptyloxy- benzoylamino)-3-[2′-(4-trifluoromethyl-phenoxy)-biphenyl-4-yl]-propionic acid 125

2-(S)-(5-Chloro-2-heptyloxy- benzoylamino)-3-(4′-dimethylamino-biphenyl-4-yl)-propionic acid 126

2-S)-(5-Chloro-2-heptyloxy- benzoylamino)-3-(3′,4′-dichloro-biphenyl-4-yl)-propionic acid 127

2-(S)-(5-Bromo-2-heptyloxy- benzoylamino)-3-[2′-(4-tert-butyl-phenoxy)-biphenyl-4-yl]-propionic acid 128

3-(3′-Chloro-4′-fluoro-biphenyl-4-yl)-2- (S)-(5-chloro-2-heptyloxy-benzoylamino)-propionic acid 129

2-(S)-(5-Chloro-2-heptyloxy- benzoylamino)-3-(4′-trifluoromethyl-biphenyl-4-yl)-propionic acid 130

2-(S)-(5-Bromo-2-cyclohexyloxy- benzoylamino)-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid methyl ester 131

2-S)-(5-Bromo-2-cyclohexyloxy- benzoylamino)-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid 132

3-Biphenyl-4-yl-2-(5-bromo-2-heptyloxy- benzoylamino)-propionic acid 133

3-Biphenyl-4-yl-2-(S)-[2-(4-tert-butyl- benzyloxy)-5-chlorobenzoylamino]- propionic acid 134

2-(S)-[5-Bromo-2-(4-[1,2,4]triazol-1-yl- benzyloxy)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid 135

2-(S)-[5-Bromo-2-(4-tert-butyl- benzyloxy)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid 136

2-S)-(2-Benzyloxy-5-bromo- benzoylamino)-3-biphenyl-4-yl-propionic acid137

3-Biphenyl-4-yl-2-(S)-[2-(3,4-bis- benzyloxy-benzyloxy)-5-bromo-benzoylamino]-propionic acid 138

3-Biphenyl-4-yl-2-(S)-{[4-(4-tert-butyl-benzyloxy)-4′-trifluoromethyl-biphenyl-3- carbonyl]-amino}-propionicacid 139

3-Biphenyl-4-yl-2-(S)-{[4-(4-tert-butyl-benzoylamino)-3′-trifluoromethyl biphenyl-3-carbonyl]-amino}-propionicacid 140

3-Biphenyl-4-yl-2-(S)-[(5-chloro-2,4-dimethoxy-4′-trifluoromethyl-biphenyl-3- carbonyl)-amino]-propionic acid141

3-Biphenyl-4-yl-2-(S)-(3-bromo-5- chloro-2,6-dimethoxy-benzoylamino)-propionic acid 142

3-(3′-Chloro-4′-fluoro-biphenyl-4-yl)-2-(S)-[(4-methoxy-4′-trifluoromethyl-biphenyl-3-carbonyl)-amino]-propionic acid methyl ester 143

2-(S)-[(4-Acetoxy-4′-trifluoromethyl- biphenyl-3-carbonyl)-amino]-3-(3′-chloro-4′-fluoro-biphenyl-4-yl)-propionic acid methyl ester 144

N-[4-(2,4-Dichloro-6-methyl-phenoxy)-2-hydroxy-phenyl]-2-(3′-trifluoromethyl- biphenyl-4-yl)-acetamide 145

2-(4-t-butyl-1-Benzoylamino)-N-methyl- benzamide 146

2-(S)-[(3-Hydroxy-naphthalene-2-carbonyl)-(4-pyridin-3-yl-benzyl)-amino]-3-(4-pyridin-3-yl-phenyl)-propionic acid 147

3-Biphenyl-4-yl-2-(S)-{[5-(3- trifluoromethoxy-phenoxymethyl)-pyrazine-2-carbonyl]-amino}-propionic acid 148

4-Hydroxy-4′-trifluoromethyl-biphenyl-3- carboxylic acid[2-(3′-chloro-4′-fluoro- biphenyl-4-yl)-1-(R)-methoxymethyl-ethyl]-amide 149

3-[4-(4-Cyano-phenoxy)-phenyl]-2-(S)-[(4′-trifluoromethyl-biphenyl-4-carbonyl)- amino]propionic acid methylester 150

3-(4′-Trifluoromethyl-biphenyl-4-yl)-2-(S)-[4-(5-trifluoromethyl-pyridin-2-yloxy)- benzoylamino]-propionic acidmethyl 151

3-(4′-Trifluoromethoxy-biphenyl-4-yl)-2(S)-[4-(5-trifluoromethyl-pyridin-2-yloxy)- benzoylamino]-propionic acidmethyl ester

Unless otherwise indicated, the structures of examples of compounds ofFormula (I) having vacant connectivity for heteroatoms, such as oxygenand nitrogen, are assumed to have a hydrogen atom attached thereto.

As used herein, the term “lower” refers to a group having between oneand six carbons.

As used herein, the term “alkyl” refers to a straight or branched chainhydrocarbon having from one to ten carbon atoms, optionally substitutedwith substituents selected from the group consisting of halo, loweralkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, loweralkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted byalkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyloptionally substituted by alkyl, silyloxy optionally substituted byalkoxy, alkyl, or aryl, silyl optionally substituted by alkoxy, alkyl,or aryl, nitro, cyano, halogen, or lower perfluoroalkyl, multipledegrees of substitution being allowed. Such an “alkyl” group maycontaining one or more O, S, S(O), or S(O)₂ atoms. Examples of “alkyl”as used herein include, but are not limited to, methyl, n-butyl,t-butyl, n-pentyl, isobutyl, and isopropyl, and the like.

As used herein, the term “alkylene” refers to a straight or branchedchain divalent hydrocarbon radical having from one to ten carbon atoms,optionally substituted with substituents selected from the groupconsisting of halo, lower alkyl, lower alkoxy, lower alkylsulfanyl,lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, aminooptionally substituted by alkyl, carboxy, carbamoyl optionallysubstituted by alkyl, aminosulfonyl optionally substituted by alkyl,silyloxy optionally substituted by alkoxy, alkyl, or aryl, silyloptionally substituted by alkoxy, alkyl, or aryl, nitro, cyano, halogen,or lower perfluoroalkyl, multiple degrees of substitution being allowed.Such an “alkylene” group may containing one or more O, S, S(O), or S(O)₂atoms. Examples of “alkylene” as used herein include, but are notlimited to, methylene, ethylene, and the like.

As used herein, the term “alkenyl” refers to a hydrocarbon radicalhaving from two to ten carbons and at least one carbon-carbon doublebond, optionally substituted with substituents selected from the groupconsisting of halo, lower alkyl, lower alkoxy, lower alkylsulfanyl,lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, aminooptionally substituted by alkyl, carboxy, carbamoyl optionallysubstituted by alkyl, aminosulfonyl optionally substituted by alkyl,silyloxy optionally substituted by alkoxy, alkyl, or aryl, silyloptionally substituted by alkoxy, alkyl, or aryl, nitro, cyano, halogen,or lower perfluoroalkyl, multiple degrees of substitution being allowed.Such an “alkenyl” group may containing one or more O, S, S(O), or S(O)₂atoms.

As used herein, the term “alkenylene” refers to a straight or branchedchain divalent hydrocarbon radical having from two to ten carbon atomsand one or more carbon-carbon double bonds, optionally substituted withsubstituents selected from the group consisting of halo, lower alkyl,lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, loweralkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted byalkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyloptionally substituted by alkyl, silyloxy optionally substituted byalkoxy, alkyl, or aryl, silyl optionally substituted by alkoxy, alkyl,or aryl, nitro, cyano, halogen, or lower perfluoroalkyl, multipledegrees of substitution being allowed. Such an “alkenylene” group maycontaining one or more O, S, S(O), or S(O)₂ atoms. Examples of“alkenylene” as used herein include, but are not limited to,ethene-1,2-diyl, propene-1,3-diyl, methylene-1,1-diyl, and the like.

As used herein, the term “alkynyl” refers to a hydrocarbon radicalhaving from two to ten carbons and at least one carbon-carbon triplebond, optionally substituted with substituents selected from the groupconsisting of halo, lower alkyl, lower alkoxy, lower alkylsulfanyl,lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, aminooptionally substituted by alkyl, carboxy, carbamoyl optionallysubstituted by alkyl, aminosulfonyl optionally substituted by alkyl,silyloxy optionally substituted by alkoxy, alkyl, or aryl, silyloptionally substituted by alkoxy, alkyl, or aryl, nitro, cyano, halogen,or lower perfluoroalkyl, multiple degrees of substitution being allowed.Such an “alkynyl” group may containing one or more O, S, S(O), or S(O)₂atoms.

As used herein, the term “alkynylene” refers to a straight or branchedchain divalent hydrocarbon radical having from two to ten carbon atomsand one or more carbon-carbon triple bonds, optionally substituted withsubstituents selected from the group consisting of halo, lower alkyl,lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, loweralkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted byalkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyloptionally substituted by alkyl, silyloxy optionally substituted byalkoxy, alkyl, or aryl, silyl optionally substituted by alkoxy, alkyl,or aryl, nitro, cyano, halogen, or lower perfluoroalkyl, multipledegrees of substitution being allowed. Such an “alkynylene” group maycontaining one or more O, S, S(O), or S(O)₂ atoms. Examples of“alkynylene” as used herein include, but are not limited to,ethyne-1,2-diyl, propyne-1,3-diyl, and the like.

As used herein, “cycloalkyl” refers to a alicyclic hydrocarbon groupoptionally possessing one or more degrees of unsaturation, having fromthree to twelve carbon atoms, optionally substituted with substituentsselected from the group consisting of halo, lower alkyl, lower alkoxy,lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo,hydroxy, mercapto, amino optionally substituted by alkyl, carboxy,carbamoyl optionally substituted by alkyl, aminosulfonyl optionallysubstituted by alkyl, nitro, cyano, halogen, or lower perfluoroalkyl,multiple degrees of substitution being allowed. “Cycloalkyl” includes byway of example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, or cyclooctyl, and the like.

As used herein, the term “cycloalkylene” refers to an non-aromaticalicyclic divalent hydrocarbon radical having from three to twelvecarbon atoms and optionally possessing one or more degrees ofunsaturation, optionally substituted with substituents selected from thegroup consisting of halo, lower alkyl, lower alkoxy, loweralkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy,mercapto, amino optionally substituted by alkyl, carboxy, carbamoyloptionally substituted by alkyl, aminosulfonyl optionally substituted byalkyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degreesof substitution being allowed. Examples of “cycloalkylene” as usedherein include, but are not limited to, cyclopropyl-1,1-diyl,cyclopropyl-1,2-diyl, cyclobutyl-1,2-diyl, cyclopentyl-1,3-diyl,cyclohexyl-1,4-diyl, cycloheptyl-1,4-diyl, or cyclooctyl-1,5-diyl, andthe like.

As used herein, the term “heterocyclic” or the term “heterocyclyl”refers to a three to twelve-membered heterocyclic ring optionallypossessing one or more degrees of unsaturation, containing one or moreheteroatomic substitutions selected from S, SO, SO₂, O, or N, optionallysubstituted with substituents selected from the group consisting ofhalo, lower alkyl, lower alkoxy, lower alkylsulfanyl, loweralkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, aminooptionally substituted by alkyl, carboxy, carbamoyl optionallysubstituted by alkyl, aminosulfonyl optionally substituted by alkyl,nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees ofsubstitution being allowed. Such a ring may be optionally fused to oneor more of another “heterocyclic” ring(s) or cycloalkyl ring(s).Examples of “heterocyclic” include, but are not limited to,tetrahydrofuran, 1,4-dioxane, 1,3-dioxane, piperidine, pyrrolidine,morpholine, piperazine, and the like.

As used herein, the term “heterocyclylene” refers to a three totwelve-membered heterocyclic ring diradical optionally having one ormore degrees of unsaturation containing one or more heteroatoms selectedfrom S, SO, SO₂, O, or N, optionally substituted with substituentsselected from the group consisting of halo, lower alkyl, lower alkoxy,lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo,hydroxy, mercapto, amino optionally substituted by alkyl, carboxy,carbamoyl optionally substituted by alkyl, aminosulfonyl optionallysubstituted by alkyl, nitro, cyano, halogen, or lower perfluoroalkyl,multiple degrees of substitution being allowed. Such a ring may beoptionally fused to one or more benzene rings or to one or more ofanother “heterocyclic” rings or cycloalkyl rings. Examples of“heterocyclylene” include, but are not limited to,tetrahydrofuran-2,5-diyl, morpholine-2,3-diyl, pyran-2,4-diyl,1,4-dioxane-2,3-diyl, 1,3-dioxane-2,4-diyl, piperidine-2,4-diyl,piperidine-1,4-diyl, pyrrolidine-1,3-diyl, morpholine-2,4-diyl,piperazine-1,4-dyil, and the like.

As used herein, the term “aryl” refers to a benzene ring or to anoptionally substituted benzene ring system fused to one or moreoptionally substituted benzene rings, optionally substituted withsubstituents selected from the group consisting of halo, lower alkyl,lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, loweralkylsulfonyl, oxo, —CH═CH—CO₂R₁, —C(O)R₁, —C(O)C(O)R₁, —C(O)C(O)OR₁,—C(O)C(O)NR₁R₂, alkyl ketones, ketoesters, keto amides, alkylene ketoesters, alkylene ketoamides, carboxy esters, hydroxy, mercapto, aminooptionally substituted by alkyl, carboxy, tetrazolyl, carbamoyloptionally substituted by alkyl, aminosulfonyl optionally substituted byalkyl, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy,alkoxycarbonyl, silyloxy optionally substituted by alkoxy, alkyl, oraryl, silyl optionally substituted by alkoxy, alkyl, or aryl, nitro,cyano, halogen, or lower perfluoroalkyl, multiple degrees ofsubstitution being allowed. Examples of aryl include, but are notlimited to, phenyl, 2-naphthyl, 1-naphthyl, 1-anthracenyl, and the like.

As used herein, the term “arylene” refers to a benzene ring diradical orto a benzene ring system diradical fused to one or more optionallysubstituted benzene rings, optionally substituted with substituentsselected from the group consisting of halo, lower alkyl, lower alkoxy,lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo,—CH═CH—CO₂R₁, —C(O)R₁, —C(O)C(O)R₁, —C(O)C(O)OR₁, —C(O)C(O)NR₁R₂, alkylketones, ketoesters, keto amides, alkylene keto esters, alkyleneketoamides, carboxy esters, hydroxy, mercapto, amino optionallysubstituted by alkyl, carboxy, tetrazolyl, carbamoyl optionallysubstituted by alkyl, aminosulfonyl optionally substituted by alkyl,acyl, aroyl, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy,alkoxycarbonyl, silyloxy optionally substituted by alkoxy, alkyl, oraryl, silyl optionally substituted by alkoxy, alkyl, or aryl, nitro,cyano, halogen, or lower perfluoroalkyl, multiple degrees ofsubstitution being allowed. Examples of “arylene” include, but are notlimited to, benzene-1,4-diyl, naphthalene-1,8-diyl, and the like.

As used herein, the term “heteroaryl” refers to a five- toseven-membered aromatic ring, or to a polycyclic heterocyclic aromaticring, containing one or more nitrogen, oxygen, or sulfur heteroatoms,where N-oxides and sulfur monoxides and sulfur dioxides are permissibleheteroaromatic substitutions, optionally substituted with substituentsselected from the group consisting of halo, lower alkyl, lower alkoxy,lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo,hydroxy, mercapto, amino optionally substituted by alkyl, carboxy,tetrazolyl, carbamoyl optionally substituted by alkyl, aminosulfonyloptionally substituted by alkyl, acyl, aroyl, heteroaroyl, acyloxy,aroyloxy, heteroaroyloxy, alkoxycarbonyl, silyloxy optionallysubstituted by alkoxy, alkyl, or aryl, silyl optionally substituted byalkoxy, alkyl, or aryl, nitro, cyano, halogen, or lower perfluoroalkyl,multiple degrees of substitution being allowed. For polycyclic aromaticring systems, one or more of the rings may contain one or moreheteroatoms. Examples of “heteroaryl” used herein are furan, thiophene,pyrrole, imidazole, pyrazole, triazole, tetrazole, thiazole, oxazole,isoxazole, oxadiazole, thiadiazole, isothiazole, pyridine, pyridazine,pyrazine, pyrimidine, quinoline, isoquinoline, quinazoline, benzofuran,benzothiophene, indole, and indazole, and the like.

As used herein, the term “heteroarylene” refers to a five- toseven-membered aromatic ring diradical, or to a polycyclic heterocyclicaromatic ring diradical, containing one or more nitrogen, oxygen, orsulfur heteroatoms, where N-oxides and sulfur monoxides and sulfurdioxides are permissible heteroaromatic substitutions, optionallysubstituted with substituents selected from the group consisting ofhalo, lower alkyl, lower alkoxy, lower alkylsulfanyl, loweralkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, aminooptionally substituted by alkyl, carboxy, tetrazolyl, carbamoyloptionally substituted by alkyl, aminosulfonyl optionally substituted byalkyl, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy,alkoxycarbonyl, silyloxy optionally substituted by alkoxy, alkyl, oraryl, silyl optionally substituted by alkoxy, alkyl, or aryl, nitro,cyano, halogen, or lower perfluoroalkyl, multiple degrees ofsubstitution being allowed. For polycyclic aromatic ring systemdiradicals, one or more of the rings may contain one or moreheteroatoms. Examples of “heteroarylene” used herein are furan-2,5-diyl,thiophene-2,4-diyl, 1,3,4-oxadiazole-2,5-diyl,1,3,4-thiadiazole-2,5-diyl, 1,3-thiazole-2,4-diyl,1,3-thiazole-2,5-diyl, pyridine-2,4-diyl, pyridine-2,3-diyl,pyridine-2,5-diyl, pyrimidine-2,4-diyl, quinoline-2,3-diyl, and thelike.

As used herein, the term “fused cycloalkylaryl” refers to a cycloalkylgroup fused to an aryl group, the two having two atoms in common, andwherein the aryl group is the point of substitution. Examples of “fusedcycloalkylaryl” used herein include 5-indanyl,5,6,7,8-tetrahydro-2-naphthyl,

and the like.

As used herein, the term “fused cycloalkylarylene” refers to a fusedcycloalkylaryl, wherein the aryl group is divalent. Examples include

and the like.

As used herein, the term “fused arylcycloalkyl” refers to an aryl groupfused to a cycloalkyl group, the two having two atoms in common, andwherein the cycloalkyl group is the point of substitution. Examples of“fused arylcycloalkyl” used herein include 1-indanyl, 2-indanyl,1-(1,2,3,4-tetrahydronaphthyl),

and the like.

As used herein, the term “fused arylcycloalkylene” refers to a fusedarylcycloalkyl, wherein the cycloalkyl group is divalent. Examplesinclude

and the like.

As used herein, the term “fused heterocyclylaryl” refers to aheterocyclyl group fused to an aryl group, the two having two atoms incommon, and wherein the aryl group is the point of substitution.Examples of “fused heterocyclylaryl” used herein include3,4-methylenedioxy-1-phenyl,

and the like

As used herein, the term “fused heterocyclylarylene” refers to a fusedheterocyclylaryl, wherein the aryl group is divalent. Examples include

and the like.

As used herein, the term “fused arylheterocyclyl” refers to an arylgroup fused to a heterocyclyl group, the two having two atoms in common,and wherein the heterocyclyl group is the point of substitution.Examples of “fused arylheterocyclyl” used herein include2-(1,3-benzodioxolyl),

and the like.

As used herein, the term “fused arylheterocyclylene” refers to a fusedarylheterocyclyl, wherein the heterocyclyl group is divalent. Examplesinclude

and the like.

As used herein, the term “fused cycloalkylheteroaryl” refers to acycloalkyl group fused to a heteroaryl group, the two having two atomsin common, and wherein the heteroaryl group is the point ofsubstitution. Examples of “fused cycloalkylheteroaryl” used hereininclude 5-aza-6-indanyl,

and the like.

As used herein, the term “fused cycloalkylheteroarylene” refers to afused cycloalkylheteroaryl, wherein the heteroaryl group is divalent.Examples include

and the like.

As used herein, the term “fused heteroarylcycloalkyl” refers to aheteroaryl group fused to a cycloalkyl group, the two having two atomsin common, and wherein the cycloalkyl group is the point ofsubstitution. Examples of “fused heteroarylcycloalkyl” used hereininclude 5-aza-1-indanyl,

and the like.

As used herein, the term “fused heteroarylcycloalkylene” refers to afused heteroarylcycloalkyl, wherein the cycloalkyl group is divalent.Examples include

and the like.

As used herein, the term “fused heterocyclylheteroaryl” refers to aheterocyclyl group fused to a heteroaryl group, the two having two atomsin common, and wherein the heteroaryl group is the point ofsubstitution. Examples of “fused heterocyclylheteroaryl” used hereininclude 1,2,3,4-tetrahydro-beta-carbolin-8-yl,

and the like.

As used herein, the term “fused heterocyclylheteroarylene” refers to afused heterocyclylheteroaryl, wherein the heteroaryl group is divalent.Examples include

and the like.

As used herein, the term “fused heteroarylheterocyclyl” refers to aheteroaryl group fused to a heterocyclyl group, the two having two atomsin common, and wherein the heterocyclyl group is the point ofsubstitution. Examples of “fused heteroarylheterocyclyl” used hereininclude -5-aza-2,3-dihydrobenzofuran-2-yl,

and the like.

As used herein, the term “fused heteroarylheterocyclylene” refers to afused heteroarylheterocyclyl, wherein the heterocyclyl group isdivalent. Examples include

and the like.

As used herein, the term “acid isostere” refers to a substituent groupthat can ionize at physiological pH to bear a net negative charge.Examples of such “acid isosteres” include but are not limited toheteroaryl groups such as, but not limited to, isoxazol-3-ol-5-yl,1H-tetrazole-5-yl, or 2H-tetrazole-5-yl. Such acid isosteres include butare not limited to heterocyclyl groups such as, but not limited to,imidazolidine-2,4-dione-5-yl, imidazolidine-2,4-dione-1-yl,1,3-thiazolidine-2,4-dione-5-yl, or 5-hydroxy-4H-pyran-4-on-2-yl.

As used herein, the term “ester isostere” refers to a substituent groupthat can be metabolically stable and can retain the selectivity andaffinity of a corresponding ester toward a target protein. Examples ofsuch “ester isosteres” include, but are not limited to, heteroarylgroups such as, but not limited to, 1,3-oxazole-5-yl, 1,3-oxazole-2-yl,1,2,3-oxadiazole-5-yl, 1,2,4-oxadiazole-5-yl, 1,3,4-oxadiazole-5-yl,1,2,3-thiadiazole-5-yl, 1,2,4-thiadiazole-5-yl, 1,3,4-thiadiazole-5-yl,5-alkyl-1,3-oxazole-2-yl, 2-alkyl-1,3-oxazole-5-yl,4-alkyl-1,2,3-oxadiazole-5-yl, 3-alkyl-1,2,4-oxadiazole-5-yl,2-alkyl-1,3,4-oxadiazole-5-yl, 4-alkyl-1,2,3-thiadiazole-5-yl,3-alkyl-1,2,4-thiadiazole-5-yl, 2-alkyl-1,3,4-thiadiazole-5-yl,1,2,4-triazole-1-yl, 3-alkyl-1,2,4-triazole-1-yl, tetrazole-1-yl, and1-alkyl-tetrazole-5-yl; aryl groups such as, but not limited to,3,5-difluoro-4-alkoxyphenyl; and heterocyclyl groups such as, but notlimited to, 1-alkyl-imidazolidine-2,4-dione-5-yl,imidazolidine-2,4-dione-1-yl, 3-alkyl-1,3-thiazolidine-2,4-dione-5-yl,and 5-alkoxy-4H-pyran-4-on-2-yl. The alkyl groups in the heterocyclyl,aryl, and heteroaryl groups of the ester isosteres may be replaced witha phenyl or alkylphenyl group.

As used herein, the term “direct bond”, where part of a structuralvariable specification, refers to the direct joining of the substituentsflanking (preceding and succeeding) the variable taken as a “directbond”.

As used herein, the term “alkoxy” refers to the group R_(a)O—, whereR_(a) is alkyl.

As used herein, the term “alkenyloxy” refers to the group R_(a)O—, whereR_(a) is alkenyl.

As used herein, the term “alkynyloxy” refers to the group R_(a)O—, whereR_(a) is alkynyl.

As used herein, the term “alkylsulfanyl” refers to the group R_(a)S—,where R_(a) is alkyl.

As used herein, the term “alkenylsulfanyl” refers to the group R_(a)S—,where R_(a) is alkenyl.

As used herein, the term “alkynylsulfanyl” refers to the group R_(a)S—,where R_(a) is alkynyl.

As used herein, the term “alkylsulfenyl” refers to the group R_(a)S(O)—,where R_(a) is alkyl.

As used herein, the term “alkenylsulfenyl” refers to the groupR_(a)S(O)—, where R_(a) is alkenyl.

As used herein, the term “alkynylsulfenyl” refers to the groupR_(a)S(O)—, where R_(a) is alkynyl.

As used herein, the term “alkylsulfonyl” refers to the group R_(a)SO₂—,where R_(a) is alkyl.

As used herein, the term “alkenylsulfonyl” refers to the groupR_(a)SO₂—, where R_(a) is alkenyl.

As used herein, the term “alkynylsulfonyl” refers to the groupR_(a)SO₂—, where R_(a) is alkynyl.

As used herein, the term “acyl” refers to the group R_(a)C(O)—, whereR_(a) is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, orheterocyclyl.

As used herein, the term “aroyl” refers to the group R_(a)C(O)—, whereR_(a) is aryl.

As used herein, the term “heteroaroyl” refers to the group R_(a)C(O)—,where R_(a) is heteroaryl.

As used herein, the term “alkoxycarbonyl” refers to the groupR_(a)OC(O)—, where R_(a) is alkyl.

As used herein, the term “acyloxy” refers to the group R_(a)C(O)O—,where R_(a) is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, orheterocyclyl.

As used herein, the term “aroyloxy” refers to the group R_(a)C(O)O—,where R_(a) is aryl.

As used herein, the term “heteroaroyloxy” refers to the groupR_(a)C(O)O—, where R_(a) is heteroaryl.

As used herein, the term “optionally” means that the subsequentlydescribed event(s) may or may not occur, and includes both event(s)which occur and events that do not occur.

As used herein, the term “substituted” refers to substitution with thenamed substituent or substituents, multiple degrees of substitutionbeing allowed unless otherwise stated.

As used herein, the terms “contain” or “containing” can refer to in-linesubstitutions at any position along the above defined alkyl, alkenyl,alkynyl or cycloalkyl substituents with one or more of any of O, S, SO,SO₂, N, or N-alkyl, including, for example, —CH₂—O—CH₂—, —CH₂—SO₂—CH₂—,—CH₂—NH—CH₃ and so forth.

Whenever the terms “alkyl” or “aryl” or either of their prefix rootsappear in a name of a substituent (e.g. arylalkoxyaryloxy) they shall beinterpreted as including those limitations given above for “alkyl” and“aryl”. Designated numbers of carbon atoms (e.g. C₁₋₁₀) shall referindependently to the number of carbon atoms in an alkyl, alkenyl oralkynyl or cyclic alkyl moiety or to the alkyl portion of a largersubstituent in which the term “alkyl” appears as its prefix root.

As used herein, the term “oxo” shall refer to the substituent ═O.

As used herein, the term “halogen” or “halo” shall include iodine,bromine, chlorine and fluorine.

As used herein, the term “mercapto” shall refer to the substituent —SH.

As used herein, the term “carboxy” shall refer to the substituent —COOH.

As used herein, the term “cyano” shall refer to the substituent —CN.

As used herein, the term “aminosulfonyl” shall refer to the substituent—SO₂NH₂.

As used herein, the term “carbamoyl” shall refer to the substituent—C(O)NH₂.

As used herein, the term “sulfanyl” shall refer to the substituent —S—.

As used herein, the term “sulfenyl” shall refer to the substituent—S(O)—.

As used herein, the term “sulfonyl” shall refer to the substituent—S(O)₂—.

As used herein, the term “solvate” is a complex of variablestoichiometry formed by a solute (in this invention, a compound ofFormula (I)) and a solvent. Such solvents for the purpose of theinvention may not sunstantially interfere with the biological activityof the solute. Solvents may be, by way of example, water, ethanol, oracetic acid.

As used herein, the term “biohydrolyzable ester” is an ester of a drugsubstance (in this invention, a compound of formula (I)) which either a)does not interfere with the biological activity of the parent substancebut confers on that substance advantageous properties in vivo such asduration of action, onset of action, and the like, or b) is biologicallyinactive but is readily converted in vivo by the subject to thebiologically active principle. The advantage is that, for example, thebiohydrolyzable ester is orally absorbed from the gut and is transformedto Formula (I) in plasma. Many examples of such are known in the art andinclude by way of example lower alkyl esters (e.g., C₁-C₄), loweracyloxyalkyl esters, lower alkoxyacyloxyalkyl esters, alkoxyacyloxyesters, alkyl acylamino alkyl esters, and choline esters.

As used herein, the term “biohydrolyzable amide” is an amide of a drugsubstance (in this invention, a compound of general formula (I)) whicheither a) does not interfere with the biological activity of the parentsubstance but confers on that substance advantageous properties in vivosuch as duration of action, onset of action, and the like, or b) isbiologically inactive but is readily converted in vivo by the subject tothe biologically active principle. The advantage is that, for example,the biohydrolyzable amide is orally absorbed from the gut and istransformed to Formula (I) in plasma. Many examples of such are known inthe art and include by way of example lower alkyl amides, .alpha-aminoacid amides, alkoxyacyl amides, and alkylaminoalkylcarbonyl amides.

As used herein, the term “prodrug” includes biohydrolyzable amides andbiohydrolyzable esters and encompasses a) compounds in which thebiohydrolyzable functionality in such a prodrug is encompassed in thecompound of formula (I) and b) compounds which may be oxidized orreduced biologically at a given functional group to yield drugsubstances of formula (I). Examples of these functional groups include,but are not limited to, 1,4-dihydropyridine,N-alkylcarbonyl-1,4-dihydropyridine, 1,4-cyclohexadiene, tert-butyl, andthe like.

The present invention also provides a method for the synthesis ofcompounds useful as intermediates in the preparation of compounds ofFormula (I) along with methods for the preparation of compounds ofFormula (I). The compounds can be prepared according to the followingreaction Schemes and procedures in which variables are as defined. Inthese reactions, it is also possible to make use of variants that arethemselves known to those of ordinary skill in this art, but are notmentioned in greater detail.

Scheme I describes the synthesis of an intermediate of structure (4).Ar₃ and Ar₄ are, independently, groups such as, but not limited to, aheteroaryl or aryl ring system. As shown in Scheme I, in one embodiment,bromo- or iodo-substituted aryl alanine methyl ester (or amino acidesterified in linkage to Wang resin) (1) is treated with a carboxylicacid in the presence of a coupling reagent, such as, but not limited to,diisopropyl carbodiimide (DIC) to form the amide (2). The resultingamide is then subjected to coupling with an arylboronic acid in thepresence of a catalyst such as, but not limited to,tetrakis(triphenylphosphine)palladium (0), in the presence of base suchas, but not limited to, sodium carbonate to form compound (3). Themethyl ester (3) is hydrolyzed using a base such as, but not limited to,LiOH to provide the free carboxylic acid (4), where Ar₁ and Ar₂ are asdefined for Formula (I).

Scheme II describes the preparation of a compound of structure (4). Ar₃and Ar₄ are, independently, groups such as, but not limited to, aheteroaryl or aryl ring system. As shown in Scheme II, in anotherembodiment, an aryl hydroxy amino acid methyl ester (or amino acidesterified in linkage to Wang resin) (5) is treated with a carboxylicacid Ar₂—CO₂H in the presence of a coupling reagent such as, but notlimited to, diisopropyl carbodiimide (DIC) to form the amide (6). Theresulting amide is then subjected to: 1) nucleophilic substitutions withan optionally substituted electron—deficient fluoroaromatic orfluoroheteroaromatic in the presence of base such as, but not limitedto, potassium carbonate; or 2) coupling with an aryl bromide, orheteroaryl bromide, and copper iodide in the presence of a baseincluding, but not limited to, cesium carbonate to form compound (7).The methyl ester in (7) is hydrolyzed using a base such as LiOH toprovide the free carboxylic acid (4), where Ar₁ and Ar₂ are as definedfor Formula (I)

Scheme III describes the preparation of a compouind of formula (4). Ar₅and Ar₆ are, independently, groups such as, but not limited to, aheteroaryl or aryl ring system. As shown in Scheme l1l, in anotherembodiment, an amino acid methyl ester (or, alternately, an amino acidesterified in linkage to Wang resin) (8) is treated with abromo-substituted aryl carboxylic acid in the presence of a couplingreagent such as, but not limited to, diisopropyl carbodiimide (DIC) toform the amide (9). The resulting amide then is subjected to couplingwith an arylboronic acid or heteroarylboronic acid in the presence of acatalyst such as, but not limited to,tetrakis(triphenylphosphine)palladium(0), in the presence of base suchas, but not limited to, sodium carbonate to form compound (10). Themethyl ester (10) is hydrolyzed using a base such as, but not limitedto, LiOH to provide the free carboxylic acid (4), where Ar₁ and Ar₂ areas defined for Formula (I).

Scheme IV describes the synthesis of a compound of formula (4). Ar₃,Ar₇, Ar₅ and Ar₆ are, independently, groups such as, but not limited to,a heteroaryl or aryl ring system. As shown in Scheme IV, in anotherembodiment, a bromo or iodo aryl alanine methyl ester (or amino acidesterified in linkage to Wang resin) (11) is subjected to coupling withan arylboronic acid in the presence of a catalyst such as, but notlimited to, tetrakis(triphenylphosphine)palladium(0), in the presence ofbase such as, but not limited to, sodium carbonate to form compound(12). The resulting compound is treated with a bromo- oriodo-substituted aryl carboxylic acid in the presence of a couplingreagent such as, but not limited to, diisopropyl carbodiimide (DIC) toform the amide (13). The resulting amide is then subjected to couplingwith a arylboronic acid or heteroarylboronic acid in the presence of acatalyst such as, but not limited to,tetrakis(triphenylphosphine)palladium(0), in the presence of base suchas, but not limited to, sodium carbonate, and the product methyl esteris hydrolyzed using a base such as LiOH to provide the free carboxylicacid (4), where Ar₁ and Ar₂ are as defined for Formula (I).

Scheme V describes the preparation of a compound of formula (16). Ar₃and Ar₇ are, independently, groups such as, but not limited to, aheteroaryl or aryl ring system. Pol is a functionalized polymericsupport, such as, but not limited to, Wang Resin. As shown in Scheme V,in another embodiment, a hydroxy aryl ester loaded onto the Wang Bromoresin or Merrifield resin using base such as, but not limited to, sodiummethoxide in DMA, and hydrolyzed to give (14), is coupled with a bromo-or iodo-subsituted aryl amino acid methyl ester (11) in the presence ofa coupling reagent such as, but not limited to, diisopropyl carbodiimide(DIC) to give the amide (15). The resulting amide (15) is then subjectedto a coupling with an arylboronic acid or heteroarylboronic acid in thepresence of a catalyst such as, but not limited to,tetrakis(triphenylphosphine)palladium(0), in the presence of base suchas, but not limited to, sodium carbonate followed by cleavage from theresin with TMSBr/TFA/DCM (1:1:1) or a similar suitable cleavage cocktailto yield the desired product (16), where Ar₁ and Ar₂ are as defined forFormula (I).

Scheme VI describes the preparation of a compound of formula (19). Ar₆and Ar₈ are, independently, groups such as, but not limited to, aheteroaryl or aryl ring system. Pol is a functionalized polymericsupport, such as, but not limited to, Wang Resin. As shown in Scheme VI,in another embodiment, a hydroxy aryl ester loaded onto the Wang Bromoresin, Merrifiend resin, or other suitable support using base such as,but not limited to, sodium methoxide in DMA, is hydrolyzed to give (17),and is coupled with an amino acid methyl ester (8) in the presence of acoupling reagent such as, but not limited to, diisopropyl carbodiimide(DIC) to give the amide (18). The resulting amide (18) is then subjectedto a coupling with an arylboronic acid or heteroarylboronic acid in thepresence of a catalyst such as, but not limited to,tetrakis(triphenylphosphine)palladium(0), in the presence of base suchas, but not limited to, sodium carbonate, and is then cleaved from theresin with TMSBr/TFA/DCM (1:1:1) or a similar suitable cleavage cocktailto yield the desired product (19), where Ar₁ and Ar₂ are as defined forFormula (I).

Scheme VII describes the synthesis of a compound of formula (23). Ar₆,Ar₇, and Ar₈ are, independently, groups such as, but not limited to, aheteroaryl or aryl ring system. Pol is a functionalized polymericsupport, such as, but not limited to, Wang Resin. As shown in SchemeVII, in another embodiment, a bromo hydroxy aryl ester (20) loaded ontoWang Bromo resin, Merrifield resin, or other suitable support using basesuch as, but not limited to, sodium methoxide in DMF, is then subjectedto a coupling with an arylboronic acid or heteroarylboronic acid in thepresence of a catalyst such as, but not limited to,tetrakis(triphenylphosphine)plladium(0), in the presence of base suchas, but not limited to, sodium carbonate, followed by hydrolysis of theproduct ester to yield the acid (21). The resulting carboxylic acid (21)is then subjected to coupling with a bromo- or iodo-substituted arylamino acid methyl ester (11) in the presence of a coupling reagent suchas, but not limited to, diisopropyl carbodiimide (DIC) to give the amide(22). The resulting amide (22) is then subjected to a coupling with anarylboronic acid or heteroaryl boronic acid in the presence of acatalyst such as, but not limited to,tetrakis(triphenylphosphine)palladium(0), in the presence of base suchas, but not limited to, sodium carbonate followed by cleavage from theresin with TMSBr/TFA/DCM (1:1:1) or a similar cleavage cocktail to yieldthe desired product (23), where Ar₁ and Ar₂ are as defined for Formula(I).

Scheme VIII describes the preparation of a compound of formula (29).Ar₇, Ar₉, Ar₁₀, and Ar₁₁ are, independently, groups such as, but notlimited to, a heteroaryl or aryl ring system. As shown in Scheme VIII,in another embodiment, a fluoro nitro phenol (24) loaded onto a polymersuch as Wang Bromo resin using base such as, but not limited to, sodiummethoxide in DMA, is then treated with a hydroxy aryl compound (25) inthe presence of base, followed by reduction of the nitro group to givethe free amine (26). The resulting amine (26) is then subjected tocoupling with a bromo- or iodo-substituted aryl acid (27) in thepresence of a coupling reagent such as, but not limited to, diisopropylcarbodiimide (DIC) to give the amide (28). The resulting amide (28) isthen subjected to a coupling with an arylboronic acid orheteroarylboronic acid in the presence of a catalyst such as, but notlimited to, tetrakis(triphenylphosphine)palladium(0), in the presence ofbase such as, but not limited to, sodium carbonate followed by cleavagefrom the resin with TMSBr/TFA/DCM (1:1:1) or a similar suitable cleavagecocktail to yield the desired product (29), where Ar₁ and Ar₂ are asdefined for Formula (I).

Scheme IX describes the preparation of a compound of formula (32). Ar₆,Ar₁₂, and Ar₁₃ are, independently, groups such as, but not limited to, aheteroaryl or aryl ring system. PG₁ is an amino protecting group such asallyloxycarbonyl or tert-butoxycarbonyl. As shown in Scheme IX, inanother embodiment, an aryl amino acid methyl ester (8) is reacted withan iodo-subsituted aryl amino carboxylic acid (the amino group of whichmay be protected with an amino protecting group PG₁ in the presence of acoupling reagent such as, but not limited to, diisopropyl carbodiimide(DIC) giving the amide (30). The amino group of the amide (30) may bethen deprotected, if desired, by treatment with, in the case of PG₁ astert-butoxycarbonyl, TFA, and is then treated with an aroyl chloride inthe presence of a base such as pyridine or TEA to give the iodo amide(31). The amide (31) is subjected to coupling with an arylboronic acidor heteroaryl boronic acid in the presence of a catalyst such as, butnot limited to, tetrakis(triphenylphosphine)palladium(0), in thepresence of base such as, but not limited to, sodium carbonate.Hydrolysis of the product methyl ester with an alkaline reagent such asLiOH provides compound (32), where Ar₁ and Ar₂ are as defined forFormula (I).

Scheme X describes the preparation of a compound of formula (37). Ar₁₄and Ar₇ are, independently, groups such as, but not limited to, aheteroaryl or aryl ring system. R is a group such as methyl,trifluromethyl, t-butyl, alkylene-sulfonyl alkyl or alkylene sulfonylaryl, aryl, heterocyclyl. As shown in Scheme X, in another embodiment, abromo or iodo aryl alanine t-butylcarbamate (or amino acid esterified inlinkage to Wang resin) (33) is subjected to coupling with an arylboronicacid in the presence of a catalyst such as, but not limited to,tetrakis(triphenylphosphine)palladium(0), in the presence of base suchas, but not limited to, sodium carbonate to form compound (34). Theresulting acid is subjected to esterification with pentafluorophenol inthe presence of a coupling reagent such as, but not limited to, DCC toform the ester, which is then treated with hydroxyamidine to yieldoxadiazole. The resulting BOC oxadiazole is deprotected using HCl toprovide the free amino oxadiazole (35). The amine is then coupled withthe methoxy substituted aryl carboxylic acid (36) in the presence of acoupling reagent such as, but not limited to, HBTU, to form the amide.The resulting amide-methyl ether is hydrolyzed using agent such as, butnot limited to, BBr₃ to provide free phenol (37), where Ar₁ and Ar₂ areas defined for formula(I).

Scheme XI describes the preparation of a compound of formula (37). Ar₃and Ar₇ are, independently, groups such as, but not limited to, aheteroaryl or aryl ring system. R is a group such as methyl,trifluromethyl, t-butyl, alkylene-sulfonyl alkyl or alkylene sulfonylaryl, aryl, heterocyclyl. As shown in Scheme XI, in another embodiment,a bromo or lodo methoxy ester (38) (as shown in Scheme VII, but startingfrom bromomethoxy arylcarboxy ester) is subjected to coupling with anarylboronic acid in the presence of a catalyst such as, but not limitedto, tetrakis(triphenylphosphine)palladium(0), in the presence of basesuch as, but not limited to, sodium carbonate to form the bisaryl esterwhich is hydrolyzed to the corresponding acid with LiOH. The resultingacid is then esterified using pentaflurophenol and in the presence ofcoupling reagent such as, but not limited to, DCC to providemethoxyester (39). The ester (39) is converted to oxadiazole usinghydroxylamidine and the resulting methoxy oxadiazole is hydrolyzed withBBr₃ to obtain the free phenol (37), where Ar₁ and Ar₂ are as definedfor formula (I).

Scheme XII describes the preparation of a compound of formula (4). Ar₁₅,Ar₁₆, and Ar₁₇ are, independently, groups such as, but not limited to, aheteroaryl or aryl ring system. As shown in Scheme XII, in anotherembodiment, a fluoro aryl aldehyde (40) is treated with a hydroxy arylcompound in the presence of base, such as, but not limited to, sodiummethoxide in DMA, to afford aryloxyaryl aldehyde (41) which is thenoxidized with oxidation agent such as, but not limited to, silvernitrate to provide aryl carboxylic acid (42). The acid (42) is subjectedto a coupling reaction with amine (8) using coupling reagent diisopropylcarbodimide (DIC) to give the amide (10). The resulting ester-amide (10)is hydrolyzed with LiOH to yield free carboxylic acid (4), where Ar₁ andAr₂ are as defined for formula (I).

Scheme XIIa describes the preparation of a compound of formula (44). Asshown in scheme XIIa, the acid (42) is coupled with an amine (43),wherein G is an acid isostere such as, but not limited to, tetrazole, oran ester isostere, such as, but not limited to, oxadiazole or oxazole,using a coupling reagent such as, but not limited to, DCC to give theamide (44), where Ar₁ and Ar₂ are as defined for formula (I).

Scheme XII describes the preparation of a compound of formula (23). Ar₆and Ar₁₈ are, independently, groups such as, but not limited to, aheteroaryl or aryl ring system. As shown in Scheme XIII, in anotherembodiment, a bromo or iododihydroxyaryl ester (45) is converted tomonohydroxyaryl ester (46) using alkylation method with alkyl halide(RBr) in the presence of base such as but not limited to, Cs₂CO₃ orMitsunobu method using alkyl alcohol in the presence ofdiethylazadicarboxylate (DEAD). The resulting bromohydroxy ester (46) issubjected to coupling with an arylboronic acid in the presence of acatalyst such as, but not limited to,tetrakis(triphenylphosphine)palladium(0), in the presence of base suchas, but not limited to, sodium carbonate to form the bisaryl ester whichis hydrolysed to the corresponding acid (47) with LiOH. The hydroxylacid (47) is then subjected to acetylation followed by acid chlorideformation using acetic anhydride and oxalyl chloride, respectively, toprovide the acid choride (48). Treatment of the acid chloride with theamine (8) in the presence of a base such as but not limited to,diisopropylethylamine, yields the amide (49), which then hydrolyzedusing LiOH to provide the free acid (23), where Ar₁ and Ar₂ are asdefined for formula (I).

Scheme XIIIa describes the preparation of a compound of formula (50). Asshown in Scheme XIIIa, the acid chloride (48) is coupled with the amine(43), wherein G is an acid isostere such as, but not limited to,tetrazole, or an ester isostere such as, but not limited to, oxadiazoleand oxazole in the presence of base such as, but not limited to DIEA togive the acetate-amide, which is then hydrolyzed using base such as butnot limited to, LiOH to provide the free phenol (50), where Ar₁ and Ar₂are as defined for formula (I).

Scheme XIV describes the preparation of a compound of formula (23). Ar₆and Ar₁₉ are, independently, groups such as, but not limited to, aheteroaryl or aryl ring system. As shown in Scheme XIV, in anotherembodiment, hydroxylaryl ester (51) is brominated using brominatingagent such as bromine but not limited to, to provide bromo ester (52).The bromohydroxy ester (52) is subjected to either Suzuki coupling withan arylboronic acid in the presence of a catalyst such as, but notlimited to, tetrakis(triphenylphosphine)palladium(0), in the presence ofbase such as, but not limited to, sodium carbonate or Stille couplingwith alkyl or aryl stananes in the presence of a catalyst such as butnot limited to, tetrakis(triphenylphosphine)palladium(0) to form thehydroxy ester which is hydrolyzed to the corresponding acid (47) withLiOH. The hydroxyl acid (47) is then subjected to acetylation followedby acid chloride formation using acetic anhydride and oxalyl chloride,respectively, to provide the acid choride (48). Treatment of the acidchloride (48) with the amine (8) in the presence of a base such as butnot limited to, diisopropylethylamine, to yield the amide (49), whichthen hydrolyzed using LiOH to provide the free acid (23), where Ar₁ andAr₂ are as defined for formula (I).

Scheme XIVa describes the preparation of a compound of formula (53). Asshown in scheme XIVa, the acid chloride (48) is coupled with the amine(43), wherein G is an acid isostere such as, but not limited to,tetrazole, and an ester isostere, (such as, but not limited to,oxadiazole and oxazole) in the presence of a base such as, but notlimited to, DIEA to give the acetate-amide, which is then hydrolyzedusing base such as, but not limited to, LiOH to provide the free phenol(53), where Ar₁ and Ar₂ are as defined for formula (I).

Scheme XV describes the preparation of a compound of formula (23). Ar₆and Ar₂₀ are, independently, groups such as, but not limited to, aheteroaryl or aryl ring system. As shown in Scheme XV, in anotherembodiment, chlorohydroxylaryl ester (54) is brominated usingbrominating agent such as bromine but not limited to, to provide bromoester which was then alkylated with Mel in the presence of base such asbut not limited to, potassium carbonate to provide dihalomethoxy ester(55). The bromomethoxy ester (55) is subjected to Suzuki coupling withan arylboronic acid in the presence of a catalyst such as but notlimited to, tetrakis(triphenylphosphine)palladium(0), in the presence ofbase such as, but not limited to, sodium carbonate to form the methoxyester which is hydrolyzed to the corresponding acid (56) with LiOH. Themethoxy acid (56) is then coupled with the amine (8) using a couplingagent such as, but not limited to, HBTU to form the amide (57). Themethyl ether (57) is then hydrolyzed using BBr₃ to yield the hydroxyacid (23), where Ar₁ and Ar₂ are as defined for formula (I).

Scheme XVa describes the preparation of a compound of formula (58). Asshown in scheme XVa, the methoxy acid (56) is coupled with a amine (43),wherein G is an acid isostere such as, but not limited to, tetrazole,and an ester isostere, (such as, but not limited to, oxadiazole andoxazole) using a coupling reagent such as, but not limited to HBTU togive the methoxyamide, which is then hydrolyzed using an agent such asbut not limited to, BBr₃ to provide the free phenol (58), where Ar₁ andAr₂ are as defined for formula(l).

Scheme XVI describes the preparation of a compound of formula (63). Ar₆and Ar₂₁ are, independently, groups such as, but not limited to, aheteroaryl or aryl ring system. As shown in Scheme XVI, in anotherembodiment, fluorobromoarylaldehyde (59) is subjected to alkylation withMel using a base such as but not limited to, potassium carbonatefollowed by oxidation using reagent such, as but not limited to,pyridinium dichromate (PDC) to provide methoxy acid which is thencoverted to the ester using esterification methods such as, but notlimited to, methanolic HCl to obtain methoxyester (60). Thedihalomethoxy ester (60) is subjected to Suzuki coupling with anarylboronic acid in the presence of a catalyst such as but not limitedto, tetrakis(triphenylphosphine)palladium(0), in the presence of basesuch as, but not limited to, sodium carbonate to form the methoxy esterwhich is hydrolyzed to the corresponding acid (61) with LiOH. Themethoxy acid (61) is then coupled with the amine (8) using couplingagent such as, but not limited, to HBTU to form the amide (62). Themethyl ether (62) is then hydrolyzed using BBr₃ to yield the hydroxylester (63), which is hydrolyzed with LiOH to provide hydroxy acid (63),where Ar₁ and Ar₂ are as defined for formula (I).

Scheme XVIa describes the preparation of a compound of formula (64). Asshown in scheme XVIa, the methoxy acid (61) is coupled with a amine(43), wherein G is an acid isostere such as, but not limited to,tetrazole, and an ester isostere, (such as, but not limited to,oxadiazole and oxazole) using a coupling reagent such as, but notlimited to, DCC to give the methoxyamide, which is then hydrolyzed usingan agent such as, but not limited to, BBr₃ to provide the free phenol(64), where Ar₁ and Ar₂ are as defined for formula (I).

Scheme XVII describes the preparation of a compound of formula (23). Ar₆and Ar₁₈ are, independently, groups such as, but not limited to, aheteroaryl or aryl ring system. As shown in Scheme XVII, in anotherembodiment, a bromo or iododihydroxyaryl ester (45) is converted tomonohydroxyaryl ester (65) using alkylation method with benzyl bromidein the presence of base such as but not limited to, Cs₂CO₃. Thebromoester (65) is then subjected to Suzuki coupling with an arylboronicacid in the presence of a catalyst such as but not limited to,tetrakis(triphenylphosphine)palladium(0), in the presence of base suchas, but not limited to, sodium carbonate to form the hydroxy ester whichis alkylated using Mel. The methoxy ester is reduced using Pd/C in thepresence of hydrogen gas to obtain the hydroxyl ester (66). The hydroxylester is then subjected to oxidative coupling using aryl boronic acid inthe presence of copper acetate to obtain aryloxy arylester which is thenhydrolyzed with LiOH to provide methoxy acid (36). The methoxy acid (36)is then coupled with the amine (8) using coupling agent such as, but notlimited to, HBTU to form the amide (57). The methyl ether (57) is thensubjected to hydrolysis using BBr₃ and subsequent ester hydrolysis withLiOH to yield the hydroxyl acid (23), where Ar₁ and Ar₂ are as definedfor formula (I).

Scheme XVIIa describes the preparation of a compound of formula (64). Asshown in scheme XVIIa, the methoxy acid (36) is coupled with a amine(43), wherein G is an acid isostere such as, but not limited to,tetrazole, and an ester isostere, (such as, but not limited to,oxadiazole and oxazole) using a coupling reagent such as, but notlimited to, HBTU to give the methoxyamide, which is then hydrolyzedusing an agent such as, but not limited to, BBr₃ to provide the freephenol (67), where Ar₁ and Ar₂ are as defined for formula (I).

Scheme XVIII describes the preparation of a compound of formula (23).Ar₆ and Ar₂₂ are, independently, groups such as, but not limited to, aheteroaryl or aryl ring system. As shown in Scheme XVIII, in anotherembodiment, a bromo or dihydroxyaryl ester (68) is treated with triflicanhydride to obtain the hydroxy triflate which is then alkylated withbenzyl bromide to get benzyloxy ester (69). The benzyloxyester (69) isthen subjected to Suzuki coupling with an arylboronic acid in thepresence of a catalyst such as but not limited to,tetrakis(triphenylphosphine)palladium(0), in the presence of base suchas, but not limited to, sodium carbonate to form the hydroxy ester whichis hydrolyzed to the corresponding acid (70) with LiOH. The benzyloxyacid (70) is then coupled with the amine (8) using coupling agent suchas, but not limited to, HBTU to form the amide (71). The benzyl ether(71) is then subjected to hydrogenolysis and hydrolysis using Pd/Ccatalyst in the presence of hydrogen and LiOH, respectively, to obtainthe free acid (23), where Ar₁ and Ar₂ are as defined for formula (I).

Scheme XVIIa describes the preparation of a compound of formula (72). Asshown in scheme XVIIIa, the benzyloxy acid (70) is coupled with a amine(43), wherein G is an acid isostere such as, but not limited to,tetrazole, and an ester isostere, (such as, but not limited to,oxadiazole and oxazole) using a coupling reagent such as, but notlimited to, HBTU to give the methoxyamide, which is then subjected tohydrogenolysis using Pd/C in the presence of hydrogen to provide thefree phenol (72), where Ar₁ and Ar₂ are as defined for formula (I).

Scheme XIX describes the preparation of a compound of formula (78). Ar₂₃is a group such as, but not limited to, a heteroaryl, aryl,alkylene-aryl, or alkyl group. As shown in Scheme XIX, in anotherembodiment, an arylaldehyde (73) is subjected to Wittig reaction toobtain the dehydroaminoester (74). The dehydroaminoester is then treatedwith Ar₂₃SH, followed by the hydrolysis using HCl to obtain theaminoester (75). The amino ester is then coupled with methoxy acid (36)using a coupling agent such as, but not limited to, HBTU, to provide theamide (76). The amide is subjected to oxidation withmetachloroperbenzoic acid and the resulting sulfone is treated with DBUto obtain methoxy ester and the methyl ether is hydrolyzed with BBr₃ toprovide the free phenol (77). The hydroxyester is hydrolyzed to freecarboxylic acid (78) using LiOH, where Ar₁ and Ar₂ are as defined forformula (I).

Scheme XX describes the preparation of a compound of formula (82). Asshown in Scheme XX, in another embodiment, the methoxy methyl ester (57)is hydrolyzed with LiOH and then coupled with N,O-dimethylhydroxylamineusing HBTU to obtain the Weinreb amide (79). The amide (79) is thenreduced with DIBAL to get the aldehyde (80). The aldehyde (80) is thensubjected to Wittig reaction to provide the alpha,beta-unsaturated ester(81). The methyl ether (81) is then hydrolyzed with BBr₃ to obtain thefree phenol (82).

Scheme XXI describes the preparation of a compound of formula (84). Asshown in Scheme XXI, in another embodiment, the Weinreb amide (79) istreated with Grignard reagent (RMgX, where R is alkyl, aryl, heteroaryland X is a halogen) to obtain the ketone (83). The methyl ether (83) ishydrolyzed with BBr₃ to get the free phenol (84).

The term “amino protecting group” as used herein refers to substituentsof the amino group commonly employed to block or protect the aminofunctionality while reacting other functional groups on the compound.Examples of such amino-protecting groups include the formyl group, thetrityl group, the phthalimido group, the trichloroacetyl group, thechloroacetyl, bromoacetyl and iodoacetyl groups, urethane-type blockinggroups such as benzyloxycarbonyl, 4-phenylbenzyloxycarbonyl,2-methylbenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl,4-fluorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl,3-chlorobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl,2,4-dichlorobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl,3-bromobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl,4-cyanobenzyloxy-carbonyl, 2-(4-xenyl)iso-propoxycarbonyl,1,1-diphenyleth-1-yloxycarbonyl, 1,1-diphenylprop-1-yloxycarbonyl,2-phenylprop-2-yloxycarbonyl, 2-(p-toluyl)prop-2-yloxycarbonyl,cyclopentanyloxycarbonyl, 1-methylcyclopentanyloxycarbonyl,cyclohexanyloxycarbonyl, 1-methylcyclohexanyloxycarbonyl,2-methylcyclohexanyloxycarbonyl, 2-(4-toluylsulfonyl)ethoxycarbonyl,2(methylsulfonyl)ethoxycarbonyl, 2-(triphenylphosphino)ethoxycarbonyl,9-fluorenylmethoxycarbonyl (“FMOC”), t-butoxycarbonyl (“BOC”),2-(trimethylsilyl)ethoxycarbonyl, allyloxycarbonyl,1-(trimethylsilylmethyl)prop-1-enyloxycarbonyl,5-benzisoxalylmethoxycarbonyl, 4-acetoxybenzyloxycarbonyl,2,2,2-trichloroethoxycarbonyl, 2-ethynyl-2-propoxycarbonyl,cyclopropylmethoxycarbonyl, 4-(decyloxy)benzyloxycarbonyl,isobornyloxycarbonyl, 1-piperidyloxycarbonyl and the like; thebenzoylmethylsulfonyl group, the 2-(nitro)phenylsulfenyl group, thediphenylphosphine oxide group and like amino-protecting groups. Thespecies of amino-protecting group employed is not critical so long asthe derivatized amino group is stable to the condition of subsequentreaction(s) on other positions of the compound of Formula (I) and can beremoved at the desired point without disrupting the remainder of themolecule. Examples of commonly used amino-protecting groups are theallyloxycarbonyl, the t-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, andthe trityl groups. Similar amino-protecting groups used in thecephalosporin, penicillin and peptide art are also embraced by the aboveterms. Further examples of groups referred to by the above terms aredescribed by J. W. Barton, “Protective Groups In Organic Chemistry”, J.G. W. McOmie, Ed., Plenum Press, New York, N.Y., 1973, and T. W. Greene,“Protective Groups in Organic Synthesis”, John Wiley and Sons, New York,N.Y., 1981. The related term “protected amino” or “protected aminogroup” defines an amino group substituted with an amino-protecting groupdiscussed above.

The term “hydroxyl protecting group” as used herein refers tosubstituents of the alcohol group commonly employed to block or protectthe alcohol functionality while reacting other functional groups on thecompound. Examples of such alcohol-protecting groups include the2-tetrahydropyranyl group, 2-ethoxyethyl group, the trityl group, thetrichloroacetyl group, urethane-type blocking groups such asbenzyloxycarbonyl, and the trialkylsilyl group, examples of such beingtrimethylsilyl, tert-butyldimethylsilyl, phenyldimethylsilyl,triiospropylsilyl and thexyldimethylsilyl. The choice of ofalcohol-protecting group employed is not critical so long as thederivatized alcohol group is stable to the condition of subsequentreaction(s) on other positions of the compound of the formulae and canbe removed at the desired point without disrupting the remainder of themolecule. Further examples of groups referred to by the above terms aredescribed by J. W. Barton, “Protective Groups In Organic Chemistry”, J.G. W. McOmie, Ed., Plenum Press, New York, N.Y., 1973, and T. W. Greene,“Protective Groups in Organic Synthesis”, John Wiley and Sons, New York,N.Y., 1981. The related term “protected hydroxyl” or “protected alcohol”defines a hydroxyl group substituted with a hydroxyl-protecting group asdiscussed above.

The term “carboxyl protecting group” as used herein refers tosubstituents of the carboxyl group commonly employed to block or protectthe —OH functionality while reacting other functional groups on thecompound. Examples of such alcohol-protecting groups include the2-tetrahydropyranyl group, 2-ethoxyethyl group, the trityl group, theallyl group, the trimethylsilylethoxymethyl group, the2,2,2-trichloroethyl group, the benzyl group, and the trialkylsilylgroup, examples of such being trimethylsilyl, tert-butyldimethylsilyl,phenyldimethylsilyl, triiospropylsilyl and thexyldimethylsilyl. Thechoice of carboxyl protecting group employed is not critical so long asthe derivatized alcohol group is stable to the condition of subsequentreaction(s) on other positions of the compound of the formulae and canbe removed at the desired point without disrupting the remainder of themolecule. Further examples of groups referred to by the above terms aredescribed by J. W. Barton, “Protective Groups In Organic Chemistry”, J.G. W. McOmie, Ed., Plenum Press, New York, N.Y., 1973, and T. W. Greene,“Protective Groups in Organic Synthesis”, John Wiley and Sons, New York,N.Y., 1981. The related term “protected carboxyl” defines a carboxylgroup substituted with a carboxyl-protecting group as discussed above.

The invention also provides pharmaceutical compositions comprising theantiviral active compounds of the invention. Thus, in anotherembodiment, the present invention comprises a pharmaceutical compositioncomprising the compound of Formula (I) and one or more pharmaceuticallyacceptable carriers, excipients, or diluents. The term “pharmaceuticalcomposition” is used herein to denote a composition that may beadministered to a mammalian host, e.g., orally, topically, parenterally,by inhalation spray, or rectally, in unit dosage formulations containingconventional non-toxic carriers, diluents, adjuvants, vehicles and thelike. The term “parenteral” as used herein, includes subcutaneousinjections, intravenous, intramuscular, intracisternal injection, or byinfusion techniques.

The compounds and compositions of the present invention may beadministered to a subject in a therapeutically effective amount. Theterm “therapeutically effective amount” is used herein to denote thatamount of a drug or pharmaceutical agent that will elicit thetherapeutic response of an animal or human that is being sought.

The pharmaceutical compositions containing a compound of the inventionmay be in a form suitable for oral use, for example, as tablets,troches, lozenges, aqueous, or oily suspensions, dispersible powders orgranules, emulsions, hard or soft capsules, or syrups or elixirs.Compositions intended for oral use may be prepared according to anyknown method, and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents, and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets may containthe active ingredient in admixture with non-toxicpharmaceutically-acceptable excipients which are suitable for themanufacture of tablets. These excipients may be for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate; granulating and disintegrating agents,for example corn starch or alginic acid; binding agents, for example,starch, gelatin or acacia; and lubricating agents, for example magnesiumstearate, stearic acid or talc. The tablets may be uncoated or they maybe coated by known techniques to delay disintegration and absorption inthe gastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate may be employed. They may also becoated by the techniques described in U.S. Pat. Nos. 4,356,108;4,166,452; and 4,265,874, to form osmotic therapeutic tablets forcontrolled release.

Formulations for oral use may also be presented as hard gelatin capsuleswhere the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or a softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions may contain the active compounds in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; ordispersing or wetting agents, such as a naturally-occurring phosphatidesuch as lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample, heptadecaethyl-eneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more coloring agents,one or more flavoring agents, and one or more sweetening agents, such assucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as a liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alchol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active compound inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example, sweetening, flavoring, and coloringagents may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, forexample, olive oil or arachis oil, or a mineral oil, for example aliquid paraffin, or a mixture thereof. Suitable emulsifying agents maybe naturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof said partial esters with ethylene oxide, for example polyoxyethylenesorbitan monooleate. The emulsions may also contain sweetening andflavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents. The pharmaceutical compositions may be in the form of a sterileinjectible aqueous or oleaginous suspension. This suspension may beformulated according to the known methods using suitable dispersing orwetting agents and suspending agents described above. The sterileinjectable preparation may also be a sterile injectable solution orsuspension in a non-toxic parenterally-acceptable diluent or solvent,for example as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that may be employed are water, Ringer's solution,and isotonic sodium chloride solution. In addition, sterile, fixed oilsare conveniently employed as solvent or suspending medium. For thispurpose, any bland fixed oil may be employed using synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid find use inthe preparation of injectables.

The compositions may also be in the form of suppositories for rectaladministration of the compounds of the invention. These compositions canbe prepared by mixing the drug with a suitable non-irritating excipientthat is solid at ordinary temperatures but liquid at the rectaltemperature and will thus melt in the rectum to release the drug. Suchmaterials include cocoa butter and polyethylene glycols, for example.

For topical use, creams, ointments, jellies, solutions of suspensions,etc., containing the compounds of the invention are contemplated. Forthe purpose of this application, topical applications shall includeeyedrops, mouth washes and gargles.

The compounds of the present invention may also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles, and multilamellar vesicles. Liposomes may beformed from a variety of phospholipids, such as cholesterol,stearylamine, or phosphatidylcholines.

Also provided by the present invention are prodrugs of the invention.

Pharmaceutically-acceptable salts of the compounds of the presentinvention, where a basic or acidic group is present in the structure,are also included within the scope of the invention. The term“pharmaceutically acceptable salts” refers to non-toxic salts of thecompounds of this invention which are generally prepared by reacting thefree base with a suitable organic or inorganic acid or by reacting theacid with a suitable organic or inorganic base. Representative saltsinclude the following salts: Acetate, Benzenesulfonate, Benzoate,Bicarbonate, Bisulfate, Bitartrate, Borate, Bromide, Calcium Edetate,Camsylate, Carbonate, Chloride, Clavulanate, Citrate, Dihydrochloride,Edetate, Edisylate, Estolate, Esylate, Fumarate, Gluceptate, Gluconate,Glutamate, Glycollylarsanilate, Hexylresorcinate, Hydrabamine,Hydrobromide, Hydrocloride, Hydroxynaphthoate, Iodide, Isethionate,Lactate, Lactobionate, Laurate, Malate, Maleate, Mandelate,Methanesulfonate, Methylbromide, Methylnitrate, Methylsulfate,Monopotassium Maleate, Mucate, Napsylate, Nitrate, N-methylglucamine,Oxalate, Pamoate (Embonate), Palmitate, Pantothenate,Phosphate/diphosphate, Polygalacturonate, Potassium, Salicylate, Sodium,Stearate, Subacetate, Succinate, Tannate, Tartrate, Teoclate, Tosylate,Triethiodide, Trimethylammonium and Valerate. When an acidic substituentis present, such as —COOH, there can be formed the ammonium,morpholinium, sodium, potassium, barium, calcium salt, and the like, foruse as the dosage form. When a basic group is present, such as amino ora basic heteroaryl radical, such as pyridyl, an acidic salt, such ashydrochloride, hydrobromide, phosphate, sulfate, trifluoroacetate,trichloroacetate, acetate, oxlate, maleate, pyruvate, malonate,succinate, citrate, tartarate, fumarate, mandelate, benzoate, cinnamate,methanesulfonate, ethanesulfonate, picrate and the like, and includeacids related to the pharmaceutically-acceptable salts listed in theJournal of Pharmaceutical Science, 66, 2 (1977) p. 1-19.

Other salts which are not pharmaceutically acceptable may be useful inthe preparation of compounds of the invention and these form a furtheraspect of the invention.

In addition, some of the compounds of Formula (I) may form solvates withwater or common organic solvents. Such solvates are also encompassedwithin the scope of the invention.

Thus, in another embodiment of the present invention, there is provideda pharmaceutical composition comprising a therapeutically effectiveamount of a compound of Formula (I), or a pharmaceutically acceptablesalt, solvate, or prodrug therof, and one or more pharmaceuticallyacceptable carriers, excipients, or diluents. In an embodiment of thepharmaceutical composition, the compound of Formula (I) is an inhibitorof smallpox virus. Thus, in one embodiment, a therapeutically effectiveamount of the compounds of Formula (I) is an amount sufficient to reduceviral load in a subject. In an embodiment, the virus is an orthopoxvirus. For example, the compounds of the present invention may be usedto inhibit smallpox infection.

In yet another embodiment, the present invention also provides apharmaceutical composition comprising a therapeutically effective amountof the compound of Formula (I), and one or more pharmaceuticallyacceptable carriers, excipients, or diluents, further comprising one ormore additional therapeutic agents. Additional therapeutic agents may bethose as described below, or may include other therapeutic agents as maybe known in the art.

The present invention also comprises a method of administering acompound of Formula (I) to a subject. In one embodiment of the method,the compound of Formula (I) is administered in an amount sufficient tosubstantially reduce the viral load in a subject. In another embodiment,the compound of Formula (I) is administered in an amount sufficient topartially reduce the viral load in said subject.

The compounds of the present invention may be effective antiviral agentspreventing, ameliorating or treating a virus infection. Embodiments ofthe present invention may therefore comprise methods for the inhibitionof a virus comprising administering to a subject in need thereof acompound of Formula (I), wherein said compound of Formula (I) isadministered to said subject as a pharmaceutical composition comprisinga therapeutically effective amount of said compound of Formula (I) andone or more pharmaceutically acceptable carriers, excipients, ordiluents. In one embodiment, a therapeutically effective amount of thecompound of Formula (I) may inhibit an orthopox virus such as smallpoxvirus. Thus, in one example embodiment, the present invention provides amethod for the inhibition of the smallpox virus comprising administeringto a subject in need thereof a compound of Formula (I), wherein thecompound of Formula (I) is administered to said subject as apharmaceutical composition comprising a therapeutically effective amountof the compound of Formula (I) and one or more pharmaceuticallyacceptable carriers, excipients, or diluents, wherein a therapeuticallyeffective amount of the compound of Formula (I) comprises an amount fortreatment or prevention of orthopox-mediated diseases or prevention ofopportunistic infections. In alternate embodiments, other types of viralinfectons may be targeted by the compounds of the present invention.

The dosage at which the compounds of Formula (I) are used may be varieddepending upon the condition being treated, the size of the individual,pharmacokinetic parameters, and the individual compound. In oneembodiment, the compound of Formula (I) may comprise a dosage such thatthe concentration of the compound of Formula (I) at the surface of avirus infected cell is about 100 micromolar (μM) or less. In anotherembodiment, the compound of Formula (I) may comprise a dosage such thatthe concentration of compound at the surface of a virus infected cell isabout 50 micromolar (μM) or less. In yet another embodiment, thecompound of Formula (I) may comprise a dosage such that theconcentration of compound at the surface of a virus infected cell isabout 10 micromolar (μM) or less.

In another embodiment, a therapeutically effective amount of thecompound of Formula (I) comprises an amount sufficient to achieve andmaintain a sustained blood level that at least partially inhibit thevirus growth. In alternate embodiments, the sustained blood levelcomprises a concentration ranging from about 0.01 μM to 200 μM, morepreferably from about 1 μM to 50 μM, and even more preferably from about10 μM to about 25 μM. In another embodiment of the method, thepharmaceutical composition further comprises one or more therapeuticagents.

The pharmaceutical compositions of the present invention may beadministered in the form of an oral dosage, a parenteral dosage unit, orby other routes. For example, in various embodiments, the compound ofFormula (I) may be administered as a dose in a range from about 0.01 to1,000 mg/kg of body weight per day, or as a dose in a range from about0.1 to 100 mg/kg of body weight per day, or as a dose in a range fromabout 0.5 to 10 mg/kg of body weight per day.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage will vary depending upon the hosttreated and the particular mode of administration. For example, aformulation intended for oral administration to humans may contain 1 mgto 2 grams of a compound of Formula (I) with an appropriate andconvenient amount of carrier material that may vary from about 5 to 95percent of the total composition. Dosage unit forms will generallycontain between from about 5 mg to about 500 mg of active ingredient.The dosage may be individualized by the clinician based on the specificclinical condition of the subject being treated. Thus, it will beunderstood that the specific dosage level for any particular patientwill depend upon a variety of factors including the activity of thespecific compound employed, the age, body weight, general health, sex,diet, time of administration, route of administration, rate ofexcretion, drug combination and the severity of the particular diseaseundergoing therapy.

As used herein, the term “subject” includes mammalian subjects such as,but not limited not, humans, cows, horses, and other agricultural livestock, and birds. In an embodiment, a subject may include one thateither suffers from one or more aforesaid diseases, disease states, orviral infections, or one that is at risk for contracting one or moreaforesaid diseases, disease states, or viral infections. Accordingly, inthe context of the method of treatment comprising administration of acompound of Formula (I) or a pharmaceutical composition comprising acompound of Formula (I) to a subject prophylactically, or prior to theonset of or diagnosis of such diseases, disease states, or viralinfections.

The term “treatment” as used herein, refers to the full spectrum oftreatments for a given disorder from which the patient is suffering,including alleviation of one, most of all symptoms resulting from thatdisorder, to an outright cure for the particular disorder or preventionof the onset of the disorder.

As used herein, the terms “virus”, “viral”, or “viral infection”includes DNA and RNA viruses

As described above, the compound of Formula (I) may be used alone, or toreplace or supplement compounds that inhibit viruses. Additionally, thecompound of Formula I may be used in conjuction with other therapeuticagents. The following is a non-exhaustive listing of adjuvants andadditional therapeutic agents that may be used in combination with theviral inhibitor of the present invention:

-   -   1. Analgesics: Aspirin    -   2. NSAIDs (Nonsteroidal anti-inflammatory drugs): Ibuprofen,        Naproxen, Diclofenac    -   3. DMARDs (Disease-Modifying Antirheumatic drugs): Methotrexate,        gold preparations, hydroxychloroquine, sulfasalazine    -   4. Biologic Response Modifiers, DMARDs: Etanercept, Infliximab    -   5. Glucocorticoids    -   6. Immunosuppresants and immunomodulators

Pharmacologic classifications of treatment for bacterial or viralinfection

-   -   1. gyrase inhibitors; ciprofloxacin    -   2. beta lactam antibiotics; cefuroxime, amoxicillin, cephalexin,        ceclor, meropenem, aztreonam    -   3. miscellaneous antibiotics; linezolid, erythromycin,        streptomycin, vancomycin, doxycycline, rifampin, isoniazid    -   4. antifungal agents; terbinafine, fluconazole, ketoconazole,        amphotericin B, griseofulvin    -   5. antiviral agents        -   a. Antiviral agents for AIDS treatment; AZT, abacavir, ddC,            ddI, d4T, 3TC, ZDV, tenofovir, nevirapine, pentafuside,            amprenavir, fosamprenavir, indinavir, nelfinavir, ritonavir,            saquanivir        -   b. Antiviral agents (general); lamivudine, foscarnet,            acyclovir, cidofovir, ganciclovir, valaciclovir

The present invention therefore provides a method of treating orpreventing viral mediated diseases including comprising administering toa subject in need thereof, a therapeutically effective amount of acompound of Formula (I) alone or in combination with therapeutic agentsselected from the group consisting of antibiotics, hormones, biologicresponse modifiers, analgesics, NSAIDs, DMARDs, glucocorticoids,immunosuppressants, immunomodulators, thrombolytic agents,antidepressants, gyrase inhibitors, beta lactam antibiotics, antifungalagents, and antiviral agents (as described above). In one embodiment,the virus targeted using the compositions of the present invention(comprising compounds of Formula (I) alone or in combination with otheragents) may comprise a pox virus. In another embodiment, the virus maycomprise smallpox.

EXAMPLES

The present invention may be further understood by reference to thefollowing non-limiting examples. Examples of compounds of the presentinvention and procedures that may be used in to prepare and identifyuseful compounds of the present invention are described below.

General Experimental:

LC-MS data was obtained using gradient elution on a Waters 600controller equipped with a 2487 dual wavelength detector and a LeapTechnologies HTS PAL Autosampler using an YMC Combiscreen ODS-A 50×4.6mm column. A three minute gradient was run from 25% B (97.5%acetonitrile, 2.5% water, 0.05% TFA) and 75% A (97.5% water, 2.5%acetonitrile, 0.05% TFA) to 100% B. The mass spectrometer used was aMicromass ZMD instrument. All data was obtained in the positive modeunless otherwise noted. ¹H NMR data was obtained on a Varian 400 MHzspectrometer. Common names and definitions for resin reagents used inthe disclosure are; Merrifield p-Chloromethyl polystyreneHydroxy-Merrifield p-Hydroxymethyl polystyrene Wang(4-Hydroxymethyl)phenoxymethyl polystyrene Wang carbonate4-(p-nitrophenyl carbonate) phenoxymethyl polystyrene Rink Resin4-(2′,4′-Dimethoxyphenyl-Fmco-aminomethyl)- phenoxy polystyrene resinWang Bromo Resin (4-Bromomethyl)phenoxymethyl polystyrene THP Resin3,4-Dihydro-2H-pyran-2-ylmethoxymethyl polystyrene

Aldehyde resin can refer to the following:

-   -   4-Benzyloxybenzaldehyde polystyrene    -   3-Benzyloxybenzaldehyde polystyrene    -   4-(4-Formyl-3-methoxyphenoxy)butyryl-aminomethyl polystyrene    -   2-(4-Formyl-3-methoxyphenoxy)ethyl polystyrene    -   2-(3,5-dimethoxy-4-formylphenoxy)ethoxy-methyl polystyrene    -   2-(3,5-dimethoxy-4-formylphenoxy)ethoxy polystyrene    -   (3-Formylindolyl)acetamidomethyl polystyrene    -   (4-Formyl-3-methoxyphenoxy) grafted        (polyethyleneglycol)-polystyrene; or    -   (4-Formyl-3-methoxyphenoxy)methylpolystyrene.

Abbreviations used in the Examples are as follows:

-   -   APCI=atmospheric pressure chemical ionization    -   BOC=tert-butoxycarbonyl    -   BOP=(1-benzotriazolyloxy)tris(dimethylamino)phosphonium        hexafluorophosphate d=day    -   DIAD=diisopropyl azodicarboxylate    -   DCC=dicyclohexylcarbodiimide    -   DCM=dichloromethane    -   DCE=dichloroethane    -   DIC=diisopropylcarbodiimide    -   DIEA=diisopropylethylamine    -   DMA=N,N-dimethylacetamide    -   DMAP=dimethylaminopyridine    -   DME=1,2 dimethoxyethane    -   DMF=N,N-dimethylformamide    -   DMPU=1,3-dimethypropylene urea    -   DMSO=dimethylsulfoxide    -   EDC=1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride    -   EDTA=ethylenediamine tetraacetic acid    -   ELISA=enzyme−linked immunosorbent assay    -   ESI=electrospray ionization    -   ether=diethyl ether    -   EtOAc=ethyl acetate    -   FBS=fetal bovine serum    -   g=gram    -   h=hour    -   HBTU=O-benzotriazol-1-yl-N,N,N′, N′-tetramethyluronium        hexafluorophosphate    -   HMPA=hexamethylphosphoric triamide    -   HOBt=1-hydroxybenzotriazole    -   Hz=hertz    -   i.v.=intravenous    -   kD=kiloDalton    -   L=liter    -   LAH=lithium aluminum hydride    -   LDA=lithium diisopropylamide    -   LPS=lipopolysaccharide    -   M=molar    -   m/z=mass to charge ratio    -   mbar=millibar    -   MeOH=methanol    -   mg=milligram    -   min=minute    -   mL=milliliter    -   mM=millimolar    -   mmol=millimole    -   mol=mole    -   mp=melting point    -   MS=mass spectrometry    -   N=normal    -   NMM=N-methylmorpholine, 4-methylmorpholine    -   NMR=nuclear magnetic resonance spectroscopy    -   p.o.=per oral    -   PBS=phosphate buffered saline solution    -   PMA=phorbol myristate acetate    -   ppm=parts per million    -   psi=pounds per square inch    -   R_(f)=relative TLC mobility    -   rt=room temperature    -   s.c.=subcutaneous    -   SPA=scintillation proximity assay    -   TEA=triethylamine    -   TFA=trifluoroacetic acid    -   THF=tetrahydrofuran    -   THP=tetrahydropyranyl    -   TLC=thin layer chromatography    -   TMSBr=bromotrimethylsilane, trimethylsilylbromide    -   T_(r)=retention time

Thus, in an embodiment, the following compounds were synthesizedaccording to the Schemes described herein.

General Procedure A:

To a solution of a carboxylic acid (1.0-1.5 mmol) in DMF (6 mL) wasadded an amino acid methyl ester (1.0-1.5 mmol), HBTU (1.0-1.5 mmol),and DIEA (2.0-3.0 mmol) and the mixture was stirred overnight. Aftercompletion of the reaction, sufficient amount of water was added and themixture was extracted with ethyl acetate (3×15 ml). The combined organiclayer was washed with water and brine, and then dried over sodiumsulfate. The solvent was removed in vacuum to afford the amide, whichwas used for further usage without further purification or purified byflash chromatography.

General Procedure B:

To a mixture of phenol and the aryl fluoride (2 eq) in DMF was addedsolid potassium carbonate or sodium methoxide (10 eq), and the mixturewas heated at 80° C. for 12 h. After completion of the reaction,sufficient amount of water was added, and the mixture was extracted withethyl acetate. The combined organic layer was washed with water andbrine, dried over sodium sulfate. The solvent was removed in vacuum andthe crude material obtained was purified by flash chromatography toafford the desired aryl ethers.

General Procedure C:

To a solution of ester in THF, CH₃OH (4:1), 2N-lithium hydroxidesolution (5 eq) was added, and the resulting reaction mixture wasstirred at 0° C. for 30 minutes and then warmed to room temperature.After completion of the reaction, 2N HCl was used to neutralize thebase, extracted with ethyl acetate, the organic layer was washed withbrine, dried over sodium sulfate, and the solvent was removed in vacuumto afford the product in pure form.

General Procedure D:

To a solution of phenyl bromide in DME were added corresponding boronicacid (5 eq), Pd (PPh₃)₄ (0.5% eq), 2N Na₂CO₃ solution (5 eq). Themixture was heated at 75° C. for 12 h. After completion of the reaction,solvent was evaporated in vacuo. During the reaction, most of the esterwas hydrolyzed to the corresponding acid. The crude product so obtainedwas re-esterfied by dissolving it in CH₃OH containing 1% of HCl. Themixture was refluxed for 6 h and after the completion of the reaction,the reaction mixture was concentrated under reduced pressure. Theresidue was purified by column chromatography (silica, CH₂Cl₂) toprovide the desired ester. The resulting ester was hydrolyzed asdescribed in procedure C yielding the pure acid.

General Procedure E:

To a solution of an aniline (1.0 mmol) in DCM (10 mL) was added asulfonyl chloride (1.0 mmol), and pyridine (10.0 mmol) and the mixturewas stirred overnight. After completion of the reaction, 50 mL of DCMwas added and the organic layer was washed with 1N HCl, saturated sodiumbicarbonate solution and brine, and then dried over sodium sulfate. Thesolvent was removed in vacuum to afford the sulfonamide, which waspurified by flash chromatography.

General Procedure F:

A flask was charged with phenol or aniline (1.0 equiv), Cu (OAc)₂ (1.0equiv), arylboronic acid (1.0-3.0), and powdered 4 A⁰ molecular sieves.The reaction mixture was diluted with CH₂Cl₂ to yield a solutionapproximately 0.1M in phenol or aniline, and the Et₃N (5.0 equiv) wasadded. After stirring the colored heterogeneous reaction mixture for 24h at 25° C. under ambient atmosphere, the resulting slurry was filteredand the diaryl ether or diaryl amine is isolated from the organicfiltrate by flash chromatography.

General Procedure G:

To a solution of a phenol (1.0 mmol) in DMF (5 mL) was added an alkylhalide (1.2 mmol) (a catalytic amount of NaI is added for alkylchloirdes), and potassium carbonate (2.5 mmol) and the mixture heated at70° C. overnight. After completion of the reaction, 5 mL of ethylacetate and 5 mL of water was added. The organic layer was washed withwater, and then dried over sodium sulfate. The solvent was removed invacuum to afford the ether, which was purified by flash chromatography.

General Procedure H:

Approximately, 10 ml of DMF per gram of resin was suspended in a roundbottomed flask. In a separate flask, 2.5 eqivalents (relative to theresin) of the carboxylic acid was dissolved in a minimum amount of DMF.Next, the same equivalent of HOBT and 0.1 equivalent of DMAP(relative tothe acid) was added. The mixture was stirred until the acid and HOBTdissolved, and then the solution was added to the resin. Next, 1.0equivalent (relative to the acid) of DIC was added to the resin mixture.The flask was equipped with a drying tube and the mixture agitated onshaker overnight. The resin was filtered in a sintered glass funnel andwashed 3 times with DMF, 3 times with methanol, and finally 3 times withDCM. The resin was in vacuo to a constant weight.

General Procedure I:

DIAD or DEAD was added dropwise to a mixture of a phenol, a primary orsecondary alcohol (1.5 eq.), and triphenylphosphine (1.5 eq.) dissolvedin anhydrous THF, at −20° C. under a nitrogen atmosphere. The mixturewas stirred for 1-2 hours while allowing to gradually warm to r.t. Thesolvent was removed and the residue purified by flash columnchromatography to afford the desired alkyl aryl ether.

General Procedure J:

To 1.0 g (2.5 mmol) of resin-bound naphthoic acid was added a mixture of1.5 g (7.5 mmol) of 4-Bromophenethylamine, 7.5 mL (7.5 mmol) of 1.0 MDIC in DMF, 7.5 mL (7.5 mmol) of 1.0 M HOBt in DMF, and a catalyticamount of DMAP. The resulting mixture was left on a shaker overnight.The resin was washed with DMF, MeOH, DCM three times of each to giveresin-bound N-2-(4-Bromophenyl)ethyl-3-hydroxyl-2-naphthamide.

General Procedure K:

To the aryl acid (5.0 mmol) solution in DCM (20 ml) and pyridine (20.0mmol) was added acetyl chloride (20.0 mmol) at −10° C. and the reactionmixture was stirred and allowed to warm up to r.t. The reaction mixturewas then poured in to icy water (50 ml) and extracted with DCM (3×50mL), organic extracts were combined, dried (Na₂SO₄), and concentrated invacuo to furnish the desired acid.

General Procedure L:

To a solution of 2-acetoxyaryl acid (10.0 mmol) solution in DCM (50 ml)was added oxalyl chloride (25.0 mmol) at −10° C. and the reactionmixture was allowed to warm up to r.t. and stirred for 2 hours. Then thereaction mixture concentrated in vacuo to furnish the desired acidchloride.

General Procedure M:

To a solution of 2-acetoxyaryl acid chloride (5.0 mmol) solution in DCE(20 ml) was added desired amine (5.0 mmol) and 4-methyl morpholine (10.0mmol). The reaction mixture was stirred at r.t. for 2 hours. Thereaction mixture was then concentrated in vacuo and poured into water(20 mL), and extracted with ethyl acetate (3×25 mL). Organic extractswere combined and concentrated in vacuo. The crude product was thenpurified with silica gel column chromatography by using ethylacetate:hexanes (5:95 to 20:80) as eluent system to afford desiredamides.

General Procedure N:

To a solution of N-Boc-protected amino acids (5.0 mmol) in methanol (20mL) was added hydrochloric acid (5 mL, 4.0 solution in dioxane) andrefluxed for 1 h. The reaction mixture was concentrated in vacuo to givethe desired amino ester. Deprotection of Boc groups and esterificationof non-amino acids are also performed using this method.

General Procedure O:

To a solution of N-Boc-amino acid (1.0 mmol) in THF (10 mL) was addedpolymer-supported DCC (2.4 g, 2.0 mmol, as a suspension in chloroform(30 mL)). This mixture was placed to a shaker and was shaken for 10 min.Then pentafluorophenol (300 mg, 1.5 mmol, 5 mL solution in THF) wasadded to the reaction mixture and placed to the shaker for 16 hours atr.t. The reaction mixture was then filtered through with celite andconcentrated in vacuo to give the pentafluoroohenyl ester. This esterwas then subjected to further manipulations without purification.

To a solution of above pentafluorophenyl ester (300 mg, 0.5 mmol) wasadded desired alkylamideoxime (1.0 mmol) and molecular sieves (100 mg)in dry chlorobenzene (20 mL). The reaction mixture was then heated at120° C. for 4-5 hours and concentrated in vacuo to remove most ofchlorobenzene. To this slurry was added DCM (50 mL) and filtered throughwith a plug of silica gel, again concentrated in vacuo. This crudeproduct was then purified with ethyl acetate:hexanes 5:95 to 10:90 togive the desired oxadiazoles.

The intermediate alkyloxyaryl oxadiazole was then deprotected usinghydrochloric acid (1 mL, 4.0 M solution in dioxane) following by generalprocedure N to give free amine. This free amine was then subjected togeneral procedure A to give the desired amides in a quantitative yield.

General Procedure P:

To a solution of alkylphenyl ether (0.2 mmol) in anhydrous DCM (10 mL)was added boron tribromide (0.5 mmol, 1.0 M solution in DCM or neat) at−78° C. and the reaction mixture stirred at −78° C. for 3 hours andallowed to warm up to the ambient temperature. After the reaction wascompleted, the reaction mixture was slowly quenched with saturatedaqueous sodium bicarbonate solution (5 mL) and extracted with DCM (3×20mL). The reaction mixture was concentrated in vacuo to give the crudeproduct. This crude product was then purified by silica gelchromatography with hexanes:ethyl acetate (from 95:5 to 80-20) as aneluent system to obtain desired phenols.

General Procedure Q:

To the phosphonate ester (1.0 mmol) in DCM was added DBU (1.0 mmol) andthe mixture was stirred for 10 min, then the aldehyde (0.9 mmol) wasadded to the mixture and stirred for another 2 h. Aqueous citric acidwas then added and the mixture was extracted with ethyl acetate (3×25mL). Organic extracts were combined and concentrated in vacuo. The crudeproduct was then purified on a silica gel column chromatography by usingethyl acetate:hexanes as eluent system to afford desired alkenes.

General Procedure R:

To a solution of an aniline (1.0 mmol) in DCE (10 mL) was added analdehyde (2.0-2.2 mmol), acetic acid (3.0 mmol), and sodiumtriacetoxyborohydride (2.5 mmol) and the mixture was stirred overnight.After completion of the reaction, 50 mL of DCM was added and the organiclayer was washed with 1N HCl, saturated sodium bicarbonate solution andbrine, and then dried over sodium sulfate. The solvent was removed invacuum to afford the amine, which was purified by flash chromatography.

The above general methods are for illustration only. Alternativeconditions that may optionally be used include: use of alternativesolvents, alternative stoichiometries of reagents, alternative reagents,alternative reaction conditions, including temperatures and alternativemethods of purification.

Synthesis of Amino Acids Synthesis of4′-Trifluoromethyl-biphenyl-4-carboxylic acid

The title compound was prepared following procedure D using 4-bromobenzoic acid (10 g, 50 mmol), 4-trifluoromethyl boronic acid (14.1g, 75mmol), palladium tetrakis-triphenylphosphine (6.0, 10 mol %) and 2NNa₂CO₃ aq.solution (150 ml, 140 mmol) in 500 ml of toluene. 9.9 g oftitle compound was isolated after usual work up.

(2S)-Amino-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid methyl ester

The title compound was prepared following procedure D using(L)-4-bromophenylalanine (8.55 g, 35.0 mmol), 2-phenoxyphenyl boronicacid (10.00 g, 46.73 mmol), palladium tetrakis-triphenylphosphine (4.09, 10% mmol) ) and 2N Na₂CO₃ aq. solution (70 mL, 140 mmol) in 140 ml ofDME. After removal of solvents, the solid was washed with ether toafford the tile compound in HCl salt form (10.0 g, 26.20 mmol).

Example 1 3-Biphenyl-4-yl-(2S)-[(3′-chloro-4′-fluoro-4-hydroxy-biphenyl-3-carbonyl)-amino]-propionic acid methyl ester

To 40 g (200 mmol) of 5-bromo-2-hydroxy-benzoic acid methyl ester, 11.0g (220 mmol) of sodium methoxide in 500 mL of anhydrous DMA was added13.30 g (71 mmol) of Merrifield resin. The mixture was heated at 110° C.overnight. The resin was washed with H₂O, DMF, MeOH, DCM three times ofeach, and dried.

To 1.0 g (2.5 mmol) of resin-bound 5-bromo-2-hydroxy-benzoic acid wasadded 1.92 g (7.5 mmol) of (2S)-amino-3-biphenyl-4-yl-propionic acidmethyl ester following general procedure A to give resin-bound3-(biphenyl-4-yl)-(2S)-(5-bromo-4-hydroxy-benzoylamino)-propionic acidmethyl ester.

The resin-bound3-(biphenyl-4-yl)-(2S)-(5-bromo-4-hydroxy-benzoylamino)-propionic acidmethyl ester (50 mg, 0.3 mmol) was reacted with3-chloro-4-fluorophenylboronic acid (240 mg, 1.5 mmol) following generalprocedure D, cleaved with TMSBr/TFA/DCM (1:1:5) at rt for 4 h. Theresidue obtained after removing the solvent was purified bychromatography to give 35 mg of title compound.

¹H-NMR(400 MHz, CDCl₃): 3.33 (t, 2H), 3.83 (s, 3H), 5.10 (m, 1H), 6.83(d, 1H), 7.35 (m, 2H), 7.22 (d, 2H), 7.29 (m, 1H), 7.35 (m, 2H), 7.43(m, 2H), 7.48 (dd, 1H), 7.55 (m, 5H); LC/MS (m/z): 504 (M+1)⁺.

Example 2 4-Hydroxy-4′-trifluoromethyl-biphenyl-3-carboxylic acidbiphenyl-4-yl-1(S)-formyl-ethyl)-amide; compound with methoxymethane

The resin-bound3-(biphenyl-4-yl)-(2S)-(5-bromo-4-hydroxy-benzoyl-amino)-propionic acidmethyl ester (30 mg, 0.09 mmol) obtained as in Example 1 was reactedwith 4-trifluoromethyl-phenyl boronic acid (86 mg, 0.45 mmol) asdescribed in the general procedure D to provide the title compound (25mg).

¹H-NMR(400 MHz, CDCl₃): 3.35 (m, 2H), 3.84 (s, 3H), 5.10 (m, 1H), 6.79(d, 1H), 7.09 (d, 1H), 7.21 (d, 2H), 7.37 (m, 1H), 7.43 (m, 3H), 7.56(m, 8H), 7.64 (dd, 1H); LC/MS (m/z): 520 (M+1)⁺.

Example 32-(S)-[(4-Hydroxy-4′-trifluoromethyl-biphenyl-3-carbonyl)-amino]-3-(4′-trifluoromethyl-biphenyl-4-yl)propionicacid methyl ester

The resin-bound3-(4-bromo-phenyl)-(2S)-[(4′-trifluoromethyl-4-hydroxy-biphenyl-3-carbonyl)-amino]-propionicacid methyl ester (30 mg, 0.09 mmol) prepared as described in Example 1was reacted with 4-trifluoromethyl-phenyl boronic acid (86 mg, 0.45mmol) by following procedure D to give the title compound (24 mg).

¹H NMR (400 MHz, CDCl₃): 3.30-3.42 (m, 2H), 3.84 (s, 3H), 5.11 (dd, 1H,J=12.8, 5.2 Hz), 6.82 (d, 1H, J=7.2 Hz), 7.10 (d, 1H, J=8.8 Hz),7.43-7.45 (m, 2H), 7.53-7.57 (m, 5H), 7.60-7.70 (m, 7H); LC/MS (m/z):588 (M+1)⁺.

By analogous methods to those described above, the following compoundswere synthesized. LC/MS EX. NAME (m/z)  43-Biphenyl-4-yl-(2S)-[(4-hydroxy-3′-nitro-biphenyl-3-carbonyl)-amino]-499 propionic acid methyl ester  53-Biphenyl-4-yl-2-(S)-[(4-hydroxy-4′-trifluoromethoxy-biphenyl- 5363-carbonyl)-amino]-propionic acid methyl ester  63-Biphenyl-4-yl-2-(S)-[(4′-fluoro-4-hydroxy-biphenyl-3- 470carbonyl)-amino]-propionic acid methyl ester  73-Biphenyl-4-yl-2-(2S)-[(3′-fluoro-4-hydroxy-biphenyl-3- 470carbonyl)-amino]-propionic acid methyl ester  83-Biphenyl-4-yl-2-(2S)-[(4-hydroxy-3′,5′-bis-trifluoromethyl- 588biphenyl-3-carbonyl)-amino]-propionic acid methyl ester  93-Biphenyl-4-yl-2-(2S)-[(3′,5′-difluoro-4-hydroxy-biphenyl-3- 488carbonyl)-amino]-propionic acid methyl ester 102-(2S)-[(3′-Chloro-4′-fluoro-4-hydroxy-biphenyl-3-carbonyl)- 572amino]-3-(4′-trifluoromethyl-biphenyl-4-yl)-propionic acid methyl ester11 2-(2S)-(5-Benzo[1,3]dioxol-5-yl-2-hydroxy-benzoylamino)-3- 496biphenyl-4-yl-propionic acid methyl ester 123-(3′-Chloro-4′-fluoro-biphenyl-4-yl)-2-(2S)-[(4-hydroxy-4′- 572trifluoromethyl-biphenyl-3-carbonyl)-amino]-propionic acid methyl ester13 3-(3′,5′-Bis-trifluoromethyl-biphenyl-4-yl)-2-(2S)-[(3′-chloro-4′-640 fluoro-4-hydroxy-biphenyl-3-carbonyl)-amino]-propionic acid methylester 143-(3′,5′-Bis-trifluoromethyl-biphenyl-4-yl)-2-(2S)-[(3′chloro-4′- 656fluoro-4-hydroxy-biphenyl-3-carbonyl)amino]-propionic acid methyl ester15 2-(2S)-[(3′-Chloro-4′-fluoro-4-hydroxy-biphenyl-3-carbonyl)- 558amino]-3-(3′-trifluoromethyl-biphenyl-4-yl)-propionic acid 162-(2S)-[(4-Hydroxy-4′-trifluoromethyl-biphenyl-3-carbonyl)- 604amino]-3-(3′-trifluoromethoxy-biphenyl-4-yl)-propionic acid methyl ester17 2-(2S)-[(4-Hydroxy-3′-trifluoromethyl-biphenyl-3-carbonyl)- 588amino]-3-(3′-trifluoromethyl-biphenyl-4-yl)-propionic acid methyl ester18 3-Biphenyl-4-yl-2-(S)-[(4-hydroxy-biphenyl-3-carbonyl)-amino]- 452propionic acid methyl ester 192-(S)-[(3′-Chloro-4′-fluoro-4-hydroxy-biphenyl-3-carbonyl)- 588amino]-3-(3′-trifluoromethoxy-biphenyl-4-yl)-propionic acid methyl ester20 2-(S)-[(4-Hydroxy-2′-trifluoromethyl-biphenyl-3-carbonyl)- 588amino]-3-(2′-trifluoromethyl-biphenyl-4-yl)-propionic acid methyl ester21 3-(3′-Chloro-4′-fluoro-biphenyl-4-yl)-2-(S)-[(3′-chloro-4′-fluoro-556 4-hydroxy-biphenyl-3-carbonyl)-amino]-propionic acid methyl ester 222-(S)-[(4-Hydroxy-3′-nitro-biphenyl-3-carbonyl)-amino]-3-(3′- 542nitro-biphenyl-4-yl)-propionic acid methyl ester 232-(S)-[(4-Hydroxy-3′-trifluoromethyl-biphenyl-3-carbonyl)- 588amino]-3-(4′-trifluoromethyl-biphenyl-4-yl)-propionic acid methyl ester24 3-(3′-Chloro-4′-fluoro-biphenyl-4-yl)-2-(S)-[(4-hydroxy-3′- 572trifluoromethyl-biphenyl-3-carbonyl)-amino]-propionic acid methyl ester25 3-Biphenyl-4-yl-2-(S)-[(4-hydroxy-2′-trifluoromethyl-biphenyl-3- 520carbonyl)-amino]-propionic acid methyl ester 263-(3′,5′-Bis-trifluoromethyl-biphenyl-4-yl)-2-(S)-[(4-hydroxy-3′- 656trifluoromethyl-biphenyl-3-carbonyl)-amino]-propionic acid methyl ester27 2-(S)-[(4-Hydroxy-3′-trifluoromethyl-biphenyl-3-carbonyl)- 588amino]-3-(2′-trifluoromethyl-biphenyl-4-yl)-propionic acid methyl ester

Example 282-(2S)-[(4-Hydroxy-4′-trifluoromethyl-biphenyl-3-carbonyl)-amino]-3-(4′-nitro-biphenyl-4-yl)-propionicacid methyl ester

To 2.50 g (5.0 mmol) of resin-bound methyl 5-bromo-2-hydroxy-benzoateobtained by a similiar procedure as in Example 1 in 30 mL of DME wasadded 2.90 g (15 mmol of 4-(trifluoromethyl)phenylboronic acid, 1.12 g(1.10 mmol) of Pd(PPh₃)₄, and 15 mL (30.0 mmol) of 2N Na₂CO₃ solution.The mixture was heated to 80° C. for 12 h. The resin was washed withH₂O, DMF, MeOH, and DCM (three times of each), and was hydrolyzed byLiOH/H₂O/THF/ethanol at rt for 3 days to give the resin-bound4′-trifluoromethyl-4-hydroxy-biphenyl-3-carboxylic acid.

To 1.5 g (2.5 mmol) of above resin-bound4′-trifluoromethyl-4-hydroxy-biphenyl-3-carboxylic acid was added 1.95 g(7.5 mmol) of 4-(S)-bromophenylalanine methyl ester, 7.5 mL (7.5 mmol)of 1.0 M DIC in DMF, 7.5 mL (7.5 mmol) of 1.0 M HOBt in DMF, andcatalytic amount of DMAP. The resulting mixture was left on a shakerovernight. The resin was washed with DMF, MeOH, and DCM (three times ofeach) to give resin-bound3-(4-bromo-phenyl)-2-(S)-[(4′-trifluoromethyl-4-hydroxy-biphenyl-3-carbonyl)-amino]-propionicacid methyl ester.

To 0.05 g (0.1 mmol) of above resin-bound3-(4-bromo-phenyl)-2-(S)-[(4′-trifluoromethyl-4-hydroxy-biphenyl-3-carbonyl)-amino]-propionicacid methyl ester in 2.0 mL of DME was added 50.1 mg (0.3 mmol) of4-nitrophenylboronic acid, 30 mg (0.03 mmol) of Pd(PPh₃)₄, and 0.3 mL(0.6 mmol) of 2N Na₂CO₃ solution. The mixture was heated at 80° C. for12 h. The resin was washed with H₂O, DMF, MeOH, DCM three times of eachand cleaved with TMSBr/TFA/DCM (1:1:5) at rt for 4 h. The residueobtained after removing the solvent was purified by chromatography (100%DCM) to give 28.2 mg of the title compound. LC/MS (m/z): 565 (M+1)⁺.

By analogous methods to those described above the following compoundswere synthesized LC/MS EX. NAME (m/z) 293-(3′,4′-Difluoro-biphenyl-4-yl)-2-(S)(2-hydroxy- 4895-pyridin-3-yl-benzoylamino)-propionic acid methyl ester 302-(S)-[(4′-Amino-4-hydroxy-biphenyl-3-carbonyl)- 467amino]-3-biphenyl-4yl-propionic acid methyl ester

Example 313-Biphenyl-4-yl-2-(2S)-{2-hydroxy-5-[2-(4′-trifluoromethyl-biphenyl-3-yl)-acetylamino]-benzoylamino]propionic acid methyl ester

The resin-bound 2-hydroxy-5-nitro-benzoic acid (500 mg, 0.5 mmol)obtained by a similar procedure as in Example 1 was reacted with2-S-amino-3-biphenyl-4-yl-propionic acid methyl ester (385mg, 1.5 mmol)as described in general procedure A. The resulting resin was reduced bySnCl₂ hydrate in NMP at rt for 4 h to give the resin-bound3-biphenyl-4-yl-2-(S)-(5-amino-2-hydroxy-phenyl)carbonylamino-propionicacid methyl ester. The above resin (120 mg, 0.1 mmol) was reacted with110 mg (0.5 mmol) of 4-bromophenylacetyl chloride, followed by 58 mg(0.3 mmol) of 4-trifluormethyl-phenyl boronic acid, 30 mg (0.03 mmol) ofPd(PPh₃)₄, and 0.3 mL (0.6 mmol) of 2N Na₂CO₃ solution. The mixture washeated to 80° C. for 12 h. The resin was washed with H₂O, DMF, MeOH, andDCM (three times of each) and cleaved with TMSBr/TFA/DCM (1:1:5) at rtfor 4 h. The residue obtained after removing the solvent was purified bychromatography (100% methylene chloride) to afford 25 mg of titlecompound. LC/MS (m/z) 653 (M+1)⁺.

Example 323-Biphenyl-4-yl-2-S)-[(3′-chloro-4′-fluoro-4-hydroxy-biphenyl-3-carbonyl)-amino]-propionicacid methyl ester

3-Chloro-4-fluoro-phenylboronic acid (3.2 g, 18.4 mmol),5-bromo-2-hydroxy-benzoic acid (4.0 g, 18.4 mmol), and Pd (PPh₃)₄ (1.67g, 1.84 mmol) were dissolved in 250 mL of DME, a 1 M Na₂CO₃ solution (46mL, 46.0 mmol) added and the mixture heated to 80° C. for 20 h. Thereaction mixture was filtered, partially evaporated and EtOAc (200 mL)and 1 N HCl (100 mL) added. The organic layer washed with 1N HCl andsaturated sodium bicarbonate, dried over sodium sulfate, and evaporated.The crude material was filtered through a silica plug (THF) to give3′-chloro-4′-fluoro-4-hydroxy-biphenyl-3-carboxylic acid (2.15 g).

3-Biphenyl-4-yl-2-(S)-[(3′-chloro-4′-fluoro-4-hydroxy-biphenyl-3-carbonyl)-amino]-propionicacid methyl ester (51 mg) was prepared from3′-chloro-4′-fluoro4-hydroxy-biphenyl-3-carboxylic acid (300 mg, 1.1mmol) and 2-(S)-amino-3-biphenyl-4-yl-propionic acid methylester-hydrochloride (330 mg, 1.1 mmol) as described in general procedureA, except for an adapted work-up. After reaction completion, thereaction mixture was poured onto 100 mL of 1N HCl and 100 mL of EtOAc.The organic layer was washed with 1N HCl, saturated sodium bicarbonate,dried over sodium sulfate and evaporated. The crude material waspurified over silica gel (8:2, DCM-hexanes). LC/MS (m/z): 504 (M+1)⁺.

Example 333-biphenyl-4-yl-2-(S)-[(3′-chloro-4′-fluoro-4-hydroxy-biphenyl-3-carbonyl)-amino]-propionicacid

3-Biphenyl-4-yl-2-(S)-[(3′-chloro-4′-fluoro-4-hydroxy-biphenyl-3-carbonyl)-amino]-propionicacid methyl ester, example 32 (20 mg, 0.040 mmol) was dissolved in 5 mLof THF-MeOH (4-1), cooled to 0° C. and 1.1 equiv of 2 N LiOH added.After 45 minutes, 2.2 additional equiv of 2N LiOH was added and thereaction stirred for 60 minutes. The reaction was worked up according togeneral procedure C to give3-(S)-biphenyl-4-yl-2-(S)-[(3′-chloro-4′-fluoro-4-hydroxy-biphenyl-3-carbonyl)-amino]-propionicacid (10 mg). LC/MS (m/z): 490 (M+1)⁺.

Example 342-(S)-(5-Chloro-2-hydroxy-benzoylamino)-3-(2′-phenoxy-biphenyl-4-yl)-propionicacid methyl ester

5-Chloro-salicylic acid (2.16 g, 10 mmol) was first transformed into2-acetyl-5-chloro-salicylic acid (252 g) with acetyl chloride (2.34 g,30 mmol) and pyridine (3.95 g, 50 mmol) in DCM. The above acid (1.29 g,5.0 mmol) was converted into acid chloride by using oxayl chloride (1.97g, 15 mmol) and catalytic amount of DMF in DCM, then(2S)-Amino-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid methyl ester(1.45 g, 5.0 mmol) and DIEA (0.77 g, 6.0 mmol) were added to the acidchloride to form(2S)-[5-Chloro-2-hydroxybenzoylamine]-3-(2′-phenoxybiphenyl-4-yl)-propionicacid methyl ester (1.92 g). LC/MS: 502

Example 352-(S)-(5-Chloro-2-hydroxy-benzoylamino)-3-(2′-phenoxy-biphenyl-4-yl)-propionicacid

To a solution of the preceeding compound,2-(S)-(5-Chloro-2-hydroxy-benzoylamino)-3-(2′-phenoxy-biphenyl-4-yl)-propionicacid (10 mg, 18 μmol) in THF/MeOH was added aqueous LiOH, as describedin General procedure C which, after work-up afforded the title compound(10 mg) LCMS for C₂₈H₂₂BrNO₅: 531, 533.

Example 362-(S)-(5-Bromo-2-hydroxy-benzoylamino)-3-(4′-phenoxy-biphenyl-4-yl)-propionicacid methyl ester

The preparation of the title compound proceeds via the same protocol asin the synthesis of(2S)-(5-Chloro-2-hydroxy-benzoylamino)-3-(2′-phenoxy-biphenyl-4-yl)-propionicacid methyl ester (vide supra) with the one exception that the Suzukicoupling (General procedure D) uses 4-phenoxy-phenylboronic acid insteadof 2-phenoxy phenylboronic acid. LCMS for C₂₉H₂₄BrNO₅: 546, 548. ¹H NMR(400 MHz, CDCl₃) 11.98 (s, 1H), 7.30-7.65 (m, 8H), 7.03-7.25 (m, 7H),6.87 (d, 1H), 6.83 (d, 1H), 5.07 (dt, 1H), 3.83 (s,3H), 3.29 (qd,2H).

Example 372-(S)-(5-Bromo-2-hydroxy-benzoylamino)-3-(4′-phenoxy-biphenyl-4-yl)-propionicacid

To a solution of the preceding compound,(2S)-(5-Bromo-2-hydroxy-benzoylamino)-3-(4′-phenoxy-biphenyl-4-yl)-propionicacid methyl ester (10 mg, 18 μmol) in THF/MeOH was added aqueous LiOH,as described in General procedure C which, after work-up afforded thetitle compound,(2S)-(5-Bromo-2-hydroxy-benzoylamino)-3-(4′-phenoxy-biphenyl-4-yl)-propionicacid (10 mg ) LCMS for C₂₈H₂₂BrNO₅: 531, 533.

Example 38 5-Chloro-4-hydroxy-4′-trifluoromethyl-biphenyl-3-carboxylicacid[2-(3′-chloro-4′-fluoro-biphenyl-3-yl)-1(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide

N-Bromosuccinimide (2.38 g, 13.38 mmol) was added to a solution of3-chlorosalicylic acid (2.1 g, 12.16 mmol) in CH₃CN (10 mL) solution andstirred for 1 h. The reaction mixture was diluted with water (25 mL),solids were filtered and washed with water and dried to get5-bromo-3-chloro-2-hydroxy-benzoic acid (2.87 g).

Methyl Iodide (3.83 g, 27.04 mmol) was added to a solution of5-Bromo-3-chloro-2-hydroxy-benzoic acid (1.7 g, 6.76 mmol) and Cs₂CO₃(4.83 g, 14.86 mmol) in DMF (10 mL) and heated at 50° C. for 12 h. Thereaction mixture was diluted with EtOAc (30 mL) and filtered over celitepad. Filtrate was washed with water, brine and dried over Na₂SO₄.Solvent was removed and the residue was purified by silicagel columnchromagography to get pure 5-Bromo-3-chloro-2-methoxy-benzoic acidmethyl ester (1.56 g)

4-Trifluorophenylboronic acid (0.815 g, 4.29 mmol) was added to asolution of 5-Bromo-3-chloro-2-methoxy-benzoic acid methyl ester (1.0 g,3.57 mmol), Pd(PPh₃)₄ (0.2 g, 0.178 mmol) and CsF (1.08 g, 7.15 mmol) inDME (10 mL )and heated at 85° C. for 10 h. The reaction was diluted withEtOAc (20 mL) and filtered, filtrate was washed water, brine and driedover Na₂SO₄. The solvent was removed under reduced pressure and thesilica gel column chromatography gave pure5-Chloro-4-methoxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid methylester (0.94 g).

5-Chloro-4-methoxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid (0.62g) was prepared from5-Chloro-4-methoxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid methylester (0.7 g, 2.03 mmol) following the procedure C.

2-(R)-tert-Butoxycarbonylamino-3-(3′-chloro-4′-fluoro-biphenyl-3-yl)-propionicacid (0.93 g ) was prepared from (R)—N-Boc-3-bromophenylalanine (1.0 g,2.9 mmol) and 3-chloro-4-fluorophenylboronic acid (1.0 g, 5.8 mmol)following general procedure D.

[2-(3′-Chloro-4′-fluoro-biphenyl-3-yl)-1-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-carbamicacid tert-butylester (0.7 g )was prepared from2-tert-Butoxycarbonylamino-3-(3′-chloro-4′-fluoro-biphenyl-3-yl)-propionicacid (0.9 g, 2.2 mmol) following general procedure O.

5-Chloro-4-methoxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid[2-(3′-chloro-4′-fluoro-biphenyl-3-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide(0.087) was prepared using the general procedure A, from2-(3′-Chloro-4′-fluoro-biphenyl-3-yl)-1-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethylaminehydrochloride salt (0.077 g, 0.21 mmol, prepared from[2-(3′-Chloro-4′-fluoro-biphenyl-3-yl)-1-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-carbamicacid tert-butylester following general procedure N) and5-Chloro-4-methoxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid (0.07g, 0.21 mmol).

The title compound (0.022 g) was prepared from5-Chloro-4-methoxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid[2-(3′-chloro-4′-fluoro-biphenyl-3-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide(0.04 g, 0.062 mmol), using the general procedure P. ¹HNMR (400 MHz,CDCl₃): 2.40 (s, 3H), 3.40 (m, 2H), 5.87 (m, 1H), 7.05-7.21 (m, 4H),7.29 (m, 1H), 7.37 (t, 1H), 7.41-7.48 (m, 3H), 7.53 (d, 2H), 7.67 (d,2H), 7.76 (d, 1H), 12.04 (br s, 1H).

Example 39 5-Chloro-4-hydroxy-4′-trifluoromethyl-biphenyl-3-carboxylicacid[2-[4-(3-chloro-4-fluorophenoxy)-phenyl]-1(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide

2-tert-Butoxycarbonylamino-3-[4-(3-chloro-4-fluoro-phenoxy)-phenyl]-propionicacid (0.87 g) was prepared from Boc-D-tyrosine methyl ester (1.0 g, 3.38mmol) 3-chloro-4-fluorophenylboronic acid (1.76 g, 10.15 mmol) asdescribed in general procedure F.

[2-[4-(3-Chloro-4-fluoro-phenoxy)-phenyl]-1-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-carbamicacid tert-butyl ester (0.57 g ) was prepared from2-tert-Butoxycarbonylamino-3-[4-(3-chloro-4-fluoro-phenoxy)-phenyl]-propionicacid [0.73 g, 1.78 mmol, [which was prepared from2-tert-Butoxycarbonylamino-3-[4-(3-chloro-4-fluoro-phenoxy)-phenyl]-propionicacid methyl ester following general procedure C] by following generalprocedure O.

5-Chloro-4-methoxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid[2-[4-(3-chloro-4-fluoro-phenoxy)-phenyl]-1-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide(0.07 g) was prepared from2-[4-(3-Chloro-4-fluoro-phenoxy)-phenyl]-1-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethylaminehydrochloride [0.07 g, 0.182 mmol, which was prepared from[2-[4-(3-Chloro-4-fluoro-phenoxy)-phenyl]-1-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-carbamicacid tert-butyl ester by the hydrolysis of BOC group using the generalprocedure N] and 5-Chloro4-methoxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid (as in example42) (0.053 g, 0.18 mmol) following general procedure A.5-Chloro-4-hydroxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid[2-[4-(3-chloro-4-fluoro-phenoxy)-phenyl]-1-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide(20 mg) was obtained upon methyl ether hydrolysis using the generalprocedure P. ¹HNMR (400 MHz, CDCl₃): 2.40 (s, 3H), 3.39 (m, 2H), 5.79(dd, 1H), 6.84 (m, 1H), 6.90 (d, 2H), 7.02 (1 H), 7.04-7.17 (m, 4H),7.50 (d, 1H), 7.61 (d, 2H), 7.71 (d, 2H), 7.78 (d, 1H), 12.03 (s, 1H).

Example 403-(4′-Chloro-biphenyl-4-yl)-2-(R)-[(4-methoxy-4′-trifluoromethyl-biphenyl-3-carbonyl)-amino]-propionicacid methyl ester

3-(4′-Chloro-biphenyl-4-yl)-2-(R)-[(4-methoxy-4′-trifluoromethyl-biphenyl-3-carbonyl)-amino]-propionicacid methyl ester was synthesized from3-(4-bromo-phenyl)-2-(S)-[(4-methoxy-4′-trifluoromethyl-biphenyl-3-carbonyl)-amino]-propionicacid methyl ester (300 mg, 0.56 mmol, obtained from the coupling of4-bromophenylalanine and4-methoxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid using generalprocedure A) and 4-chlorophenyl boronic acid (156 mg, 1.0 mmol)following general procedure D. (250 mg). LC/MS (m/z): 568 (M+1)⁺.

Example 413-(4′-Chloro-biphenyl-4-yl)-2-(R)-[(4-methoxy-4′-trifluoromethyl-biphenyl-3-carbonyl)-amino]-propionicacid

The title compound was prepared from3-(4′-chloro-biphenyl-4-yl)-2-[(4-methoxy-4′-trifluoromethyl-biphenyl-3-carbonyl)-amino]-propionicacid methyl ester (250 mg, 0.44 mmol) following general procedure C.(190 mg).

LC/MS (m/z): 554 (M+1)⁺.

Example 42 4-Hydroxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid[2-(3′-chloro-biphenyl-4-yl)-1(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide

The title compound was prepared from4-methoxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid[2-(3′-chloro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide(160 mg, 0.27 mmol obtained using protocol similar to example 44)following general procedure O. (78 mg).

¹H-NMR(400 MHz, CDCl₃): 2.41 (s, 3H), 3.47 (d, 2H), 5.83 (m, 1H), 6.86(d, 1H), 7.14 (m, 3H), 7.38 (m, 4H), 7.55 (m, 5H), 7.65 (m, 3H); LC/MS(m/z): 578 (M+1)⁺.

By analogous methods to those described above the following compoundswere synthesized LC/MS EX. NAME (m/z) 434-Hydroxy-4′-trifluoromethyl-biphenyl-3-carboxylic 578 acid[2-(4′-chloro-biphenyl-4-yl)-1(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide 444-Hydroxy-4′-trifluoromethyl-biphenyl-3-carboxylic 650 acid[2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1(R)-(3-trifluoromethyl[1,2,4]oxadiazol-5-yl)-ethyl]-amide 454-Hydroxy-4′-trifluoromethyl-biphenyl-3-carboxylic 638 acid[1(R)-(3-tert-butyl-[1,2,4]oxadiazol-5-yl)-2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-ethyl]-amide

Example 465-(3′-Chloro-4′-fluoro-biphenyl-4-yl)-4-[(4-hydroxy-4′-trifluoromethyl-biphenyl-3(R)-carbonyl)amino]-pent-2-enoic acid ethyl ester

3-(3′-Chloro-4′-fluoro-biphenyl-4-yl)-2-(R)-[(4-methoxy-4′-trifluoromethyl-biphenyl-3-carbonyl)-amino]-propionicacid methyl ester (223 mg) was prepared from4-Methoxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid (141 mg, 0.5mmol) and-2-(R)-amino-3-(3′-chloro-4′-fluoro-biphenyl-4-yl)-propionicacid methyl ester (155 mg, 0.5 mmol) following the general procedure A.

LC-MS (m/z): 586 (M+1)⁺; ¹H NMR (400 MHz, CDCl₃): δ 3.24-3.38 (m, 2H),3.76 (m, 1H), 3.80 (s, 3H), 3.90 (s, 3H), 5.14 (q, 1H), 6.68 (d, 1H),7.06 (q, 1H), 7.18 (q, 1H), 7.24 (m, 3H), 7.44 (m, 2H), 7.52-7.60 (m,2H), 7.68-7.72 (m, 3H) and 8.16 (dd, 1H).

3-(3′-Chloro-4′-fluoro-biphenyl-4-yl)-2-(R)-[(4-methoxy-4′-trifluoromethyl-biphenyl-3-carbonyl)-amino]-propionicacid was obtained from the hydrolysis of the above ester using thegeneral procedure C.

4-Methoxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid[2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(methoxy-methyl-carbamoyl)-ethyl]-amide(0.078 g ) was prepared from3-(3′-Chloro-4′-fluoro-biphenyl-4-yl)-2-(R)-[(4-methoxy-4′-trifluoromethyl-biphenyl-3-carbonyl)-amino]-propionicacid (0.1 g, 0.179 mmol) and N,O-dimethylhydroxylamine hydrochloride(0.017 g, 0.179 mmol) following general procedure A

4-Methoxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid[2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-formyl-ethyl]-amide wassynthesized by the following procedure: To4-methoxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid[2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(methoxy-methyl-carbamoyl)-ethyl]-amide(85 mg, 0.14 mmol) in THF (2 mL) was added DIBAL-H (0.64 mL, 0.64 mmol,1.0 M in DCM) at −78° C. and the mixture was stirred at −78° C. for 2 h.After that potassium sodium tartrate was added and the mixture wasstirred overnight, then the mixture was extracted with ethyl acetate(3×25 mL). Organic extracts were combined and concentrated in vacuo. Thecrude product was then purified with silica gel column chromatography byusing ethyl acetate:hexanes (2:1) to afford the aldehyde intermediate(45mg). ¹H-NMR(300 MHz, CDCl₃): 3.30 (m, 2H), 3.98 (s, 3H), 4.95 (m, 1H),7.15 (m, 2H), 7.50 (m, 12H), 8.50 (s, 1H), 9.75 (s, 1H); LC/MS (m/z):556 (M+1)⁺.

5-(3′-Chloro-4′-fluoro-biphenyl-4-yl)-4-[(4-methoxy-4′-trifluoromethyl-biphenyl-3-(R)-carbonyl)-amino]-pent-2-enoicacid ethyl ester (Isomer 128 mg) and its geometrical isomer (Isomer II,15 mg) were prepared from the above,4-methoxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid[2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-formyl-ethyl]-amide (40 mg,0.072 mmol) and (diethoxy-phosphoryl)-acetic acid ethyl ester (32 mg,0.14 mmol) following general procedure Q.

Isomer I: ¹H-NMR(300 MHz, CDCl₃): 1.27 (t, 3H), 3.18 (d, 2H), 3.83 (s,3H), 4.18 (m, 2H), 5.50 (t, 1H), 1.27 (t, 3H), 3.18 (d, 2H), 3.83 (s,3H), 4.18 (m, 2H), 5.50 (t, 1H), 7.03 (d, 1H), 7.18 (m, 1H), 7.40 (m,6H), 7.60 (m, 1H), 7.69 (m, 5H), 8.46 (d, 1H), 9.08 (s, 1H); LC/MS(m/z): 626 (M+1)

Isomer II: ¹H-NMR(300 MHz, CDCl₃): 1.27 (s, 3H), 3,11 (d, 2H), 3.91 (s,3H), 4.20 (m, 2H), 5.30 (m, 1H), 5.94 (dd, 1H), 7.07 (m, 2H), 7.20 (m,1H), 7.32 (m, 3H), 7.46 (m, 2H), 7.60 (m, 1H), 7.69 (m, 4H), 8.00 (d,1H), 8.48 (d, 1H); LC/MS (m/z): 626 (M+1)⁺.

The title compound (example 50) was prepared from5-(3′-chloro-4′-fluoro-biphenyl-4-yl)-4-[(4-methoxy-4′-trifluoromethyl-biphenyl-3-(R)-carbonyl)-amino]-pent-2-enoicacid ethyl ester (Isomer II, 15 mg, 0.024 mmol) following generalprocedure P (2.5 mg).

Example 47 4-Hydroxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid[2-(3′-chloro-4′-fluoro-6-methoxy-biphenyl-3-yl)-ethyl]-amide

The resin-bound 4-hydroxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid(20 mg, 0.06 mmol) obtained as in Example 1 was reacted with3-bromo-4-methoxy-phenethyl amine (57 mg, 0.25 mmol) following generalprocedure A to give resin bound4-Hydroxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid[2-3-bromo-4-methoxy-phenyl)-ethyl]-amide(18 mg, 0.05 mmol). The aboveresin bound amide was treated with 3-chloro-4-fluoro-phenyl boronic acid(43 mg, 0.25 mmol) as described in the general procedure D to providethe title compound (8.0 mg,).

¹H-NMR(400 MHz, CDCl₃): 2.95 (t, 2H), 3.73 (dd, 2H), 3.80 (s, 3H), 6.94(d, 1H), 7.11 (m, 3H), 7.21 (dd, 1H), 7.31 (m, 1H), 7.37 (d, 1H), 7.52(m, 4H), 7.64 (m, 3H); LC/MS (m/z): 544 (M+1)⁺.

Example 482-(S)-[(4-Amino-4′-trifluoromethyl-biphenyl-3-carbonyl)-amino]-3-(3′-chloro-4′-fluoro-biphenyl-4-yl)-propionicacid methyl ester

4-Amino-4′-trifluoromethyl-biphenyl-3-carboxylic acid methyl ester (3.0g) was prepared from 2-amino-5-bromobenzoic acid methyl ester (4.58 g,20 mmol) and 4-trifluoromethylphenyl boronic acid (4.75 g, 25 mmol)following general procedure D, then hydrolyzed following generalprocedure C. The above acid (281 mg, 1.0 mmol) was reacted with2(S)-amino-3-(3′chloro-4′-fluoro-biphenyl-4-yl)-propionic acid methylester (343 mg, 1.0 mmol) as described in general procedure A to give thetitle compound. (300 mg)

¹H NMR (400 MHz, CDCl₃): 3.34 (m, 2H), 3.83 (s, 3H), 5.06 (m, 1H), 6.77(d, 1H), 7.42-7.80 (m, 11H), 7.84 (d, 2H), 8.32 (m, 1H); LC/MS (m/z):571 (M+1)⁺.

Example 493-(3′-Chloro-4′-fluoro-biphenyl-4-yl)-2-(S)-[(4-methanesulfonylamino-4′-trifluoromethyl-biphenyl-3-carbonyl)-amino]propionic acidmethyl ester

2(S)-[(4-Amino-4′trifluoromethyl-biphenyl-3-carbonyl)-amino]-3-(3′-chloro-4′-fluoro-biphenyl-4-yl)-propionicacid methyl ester (30 mg, 0.053 mmol) was reacted with methanesulfonylchloride (12 mg, 0.11 mmol) following general procedure E to give thetitle compound. (21 mg)

¹H NMR (400 MHz, CDCl₃): 3.05 (s, 3H), 3.28, 3.36 (ABX, 2H), 3.85 (s,3H), 5.07 (dd, 1H), 6.72 (d, 1H), 7.21 (m, 3H), 7.38 (m, 1H), 7.46-7.62(m, 8H), 7.71 (dd, 1H), 7.82 (d, 1H); LC/MS (m/z): 649 (M+1)⁺.

Example 50 3′-Chloro-4′-fluoro-4-hydroxy-biphenyl-3-carboxylic acid(2-biphenyl-4-yl-1(S)-methylcarbamoyl-ethyl)-amide

Resin bound3-(Biphenyl-4-yl)-(2S)-[(3′-chloro-4′-fluoro-4-hydroxy-biphenyl-3-carbonyl)-amino]-propionicacid (30 mg, 0.09 mmol) prepared from resin bound3-(Biphenyl-4-yl)-(2S)-[(3′-chloro-4′-fluoro-4-hydroxy-biphenyl3-carbonyl)-amino]-propionicacid methyl ester following general procedure C, was reacted with methylamine in THF(0.45 mmol) as described in general procedure A, thencleaved with TMSBr/TFA/DCM (1:1:5) at rt for 4 h. The residue obtainedafter removing the solvent was purified by chromatography to give thetitle compound. (36 mg). LC/MS (m/z): 503 (M+1)⁺.

By analogous methods to those described above the following compoundswere synthesized. LC/MS EX. NAME (M + 1) 513′-Chloro-4′-fluoro-4-hydroxy-biphenyl-3- 627 carboxylic acid{2-biphenyl-4-yl-1-(S)-[2-(4-chloro-phenyl)-ethylcarbamoyl]-ethyl}-amide 523′-Chloro-4′-fluoro-4-hydroxy-biphenyl-3- 529 carboxylic acid(1-(S)-allylcarbamoyl-2-biphenyl-4- yl-ethyl)-amide 532-(S)-{3-Biphenyl-4-yl-2-(S)-[(3′-chloro- 5894′-fluoro-4-hydroxy-biphenyl-3-carbonyl)amino]propionylamino}-3-methyl-butyric acid 543-(S)-{3-Biphenyl-4-yl-2-[(3′-chloro-4′- 561fluoro-4-hydroxy-biphenyl-3-carbonyl)-amino] propionylamino}-propionicacid 55 3′-Chloro-4′-fluoro-4-hydroxy-biphenyl-3- 547 carboxylic acid[2-biphenyl-4-yl-1-(S)-(2-methoxy- ethylcarbamoyl)-ethyl]-amide

Example 562-(S)-[2-(S)-[(3′-Chloro-4′-fluoro-4-hydroxy-biphenyl-3-carbonyl)-amino]-3-(3′-trifluoromethyl-biphenyl-4-yl)-propionylamino]-hexanoicacid

5-Bromomsalicylic acid (12.4 g, 57.3 mmol),3-chloro-4-fluorophenylboronic acid (10.0 g, 57.3 mmol), and palladiumtetrakistriphenylphosphine (5.2 g, 5.73 mmol) were dissolved in 200 mLDME and a 2N sodium carbonate (143.4 mL, 143.4 mmol) solution added. Thereaction mixture was stirred overnight at 75° C. The solvent was removedand 10 mL concentrated HCl was added, followed by 100 mL THF. AdditionalHCl was added until the solution was neutralized and the mixture wasfiltered through a silica gel plug to remove the catalyst. DCM was addedto the solution until the layers separated and the organic layer wasdried over magnesium sulfate and evaporated. The solid was stirred withDCM for 2 hours, filtered, washed 2× with hexanes and dried (9.1 g).

The 3′-chloro-4′-fluoro-4-hydroxy-biphenyl-3-carboxylic acid (4.56 g,17.1 mmol), 2-(S)-amino-3-(4-bromo-phenyl)-propionic acid methyl ester(5.0 g, 17.1 mmol) and HBTU (6.48 g, 17.1 mmol) were dissolved in 100 mLDMF. DIEA (5.96 mL, 34.2 mmol) was added and the mixture was stirredovernight. Ethyl acetate (200 mL) and 1N HCl (200 mL) were added to themixture and the organic layer was washed with 10% sodium carbonate,dried over sodium sulfate and evaporated. The product was purified oversilica (hexanes/ethyl acetate) (5.6 g). LC/MS (m/z): 508 [(M+1)⁺].

3-(4-bromo-phenyl)-2-(S)-[(3′-chloro-4′-fluoro-4-hydroxy-biphenyl-3-carbonyl)-amino]-propionicacid methyl ester (4.3 g, 8.49 mmol), 3-trifluoromethylphenylboronicacid (3.22 g, 16.98 mmol), and palladium tetrakistriphenylphosphine(1.54 g, 1.70 mmol) were dissolved in 200 mL DME and a 2N sodiumcarbonate (21.23 mL, 21.23 mmol) solution added. The reaction mixturewas stirred overnight at 75° C. The solvent was removed and 5 mLconcentrated HCl was added, followed by 100 mL THF. Additional HCl wasadded until solution was neutralized and the mixture was filteredthrough a silica gel plug to remove the catalyst. DCM was added to thesolution until the layers separated and the organic layer was dried overmagnesium sulfate and evaporated. The solid was stirred with DCM for 2hours, filtered, washed 2× with hexanes and dried (3.0 g). LC/MS (m/z):572 [(M+1)⁺].

2-(S)-[(3′-Chloro-4′-fluoro-4-hydroxy-biphenyl-3-carbonyl)-amino]-3-(3′-trifluoromethyl-biphenyl-4-yl)-propionicacid methyl ester (3.0 g, 5.2 mmol) was dissolved in 100 mL ofTHF-methanol (4-1), cooled to 0° C. and 20 mL 2N LiOH added. Thereaction was stirred at 0° C. for 1 hour. Ethyl acetate (100 mL) and 1NHCl (100 mL) were added to the mixture and the organic washed withbrine, dried and evaporated to give2-(S)-[(3′-chloro-4′-fluoro-4-hydroxy-biphenyl-3-carbonyl)-amino]-3-(3′-trifluoromethyl-biphenyl-4-yl)-propionicacid (2.8 g). LC/MS (m/z): 558 [(M+1)⁺].

Resin-bound fmoc-norleucine (0.08 mmol) was deprotected with 20%piperidine in DMF (25 mL) for 2 hours. The reaction mixture was drainedand washed 3× with DMF, methanol and DCM (3×15 mL each solvent).

To the resin-bound norleucine (0.08 mmol), a solution of2-(S)-[(3′-chloro-4′-fluoro-4-hydroxy-biphenyl-3-carbonyl)-amino]-3-(3′-trifluoromethyl-biphenyl-4-yl)-propionicacid (0.118 g, 0.20 mmol) in DMF (0.2 mL), HOBt (0.027 g, 0.20 mmol) inDMF (0.2 mL) and DIC (0.025 g, 0.2 mmol) in DMF (0.2 mL) were added andthe mixture was shaken overnight. The reaction mixture was drained andwashed with DMF, methanol and DCM (3×150 mL each solvent).

Resin-bound2-(S)-[2-(S)-[(3′-Chloro-4′-fluoro-4-hydroxy-biphenyl-3-carbonyl)-amino]-3-(3′-trifluoromethyl-biphenyl-4-yl)-propionylamino]-3-phenyl-propionicacid was treated with 20% TFA in DCM (2 mL) for 1 hour. The filtrate wascollected and evaporated to give2-(S)-[2-(S)-[(3′-Chloro-4′-fluoro-4-hydroxy-biphenyl-3-carbonyl)-amino]-3-(3′-trifluoromethyl-biphenyl-4-yl)-propionylamino]-3-phenyl-propionicacid. The product was purified via prep TLC (ethylacetate/methanol/acetic acid). LC/MS (m/z): 671 [(M+1)⁺].

By analogous methods to those described above the following compoundswere synthesized. LC/MS EX. NAME (M + 1) 571-[2-(S)-[(3′-Chloro-4′-fluoro-4-hydroxy-biphenyl-3- 655carbonyl)-amino]-3-(3′-trifluoromethyl-biphenyl-4-yl)-propionyl]-pyrrolidine-2-(S)-carboxylic acid 582-(S)-[2-(S)-[(3′-Chloro-4′-fluoro-4-hydroxy-biphenyl-3- 504carbonyl)-amino]-3-(3′-trifluoromethyl-biphenyl-4-yl)-propionylamino]-4-methylpentanoic acid 59{[2-(S)-[(3′-Chloro-4′-fluoro-4-hydroxy-biphenyl-3- 504carbonyl)-amino]-3-(3′-trifluoromethyl-biphenyl-4-yl)-propionyl]-methyl-amino}-acetic acid 60[2-(S)-[(3′-Chloro-4′-fluoro-4-hydroxy-biphenyl-3- 490carbonyl)-amino]-3-(3′-trifluoromethyl-biphenyl-4-yl)-propionylamino]-2-(S)-phenyl-acetic acid 612-(S)-[2-(S)-[(3′-Chloro-4′-fluoro-4-hydroxy-biphenyl-3- 721carbonyl)-amino]-3-(3′-trifluoromethyl-biphenyl-4-yl)-propionylamino]-3-(4-hydroxy-phenyl)-propionic acid 622-(S)-[2-(S)-[(3′-Chloro-4′-fluoro-4-hydroxy-biphenyl-3- 629carbonyl)-amino]-3-(3′-trifluoromethyl-biphenyl-4-yl)-propionylamino]-propionic acid 632-(S)-[2-(S)-[(3′-Chloro-4′-fluoro-4-hydroxy-biphenyl-3- 657carbonyl)-amino]-3-(3′-trifluoromethyl-biphenyl-4-yl)-propionylamino]-3-methyl-butyric acid 642-(S)-[2-(S)-[(3′-Chloro-4′-fluoro-4-hydroxy-biphenyl-3- 687carbonyl)-amino]-3-(3′-trifluoromethyl-biphenyl-4-yl)-propionylamino]-pentanedioic acid 652-(S)-[2-(S)-[(3′-Chloro-4′-fluoro-4-hydroxy-biphenyl-3- 673carbonyl)-amino]-3-(3′-trifluoromethyl-biphenyl-4-yl)-propionylamino]-succinic acid

Example 66 4-Methoxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid[2-(R)-(4-methyl-piperazin-1-yl)-2-oxo-1-(4′-trifluoromethyl-biphenyl-4-ylmethyl)-ethyl]-amide

4-Methoxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid[2-(R)-(4-methyl-piperazin-1-yl)-2-oxo-1-(4′-trifluoromethyl-biphenyl-4-ylmethyl)-ethyl]-amide(83 mg) was prepared from2-(R)-[(4-methoxy-4′-trifluoromethyl-biphenyl-3-carbonyl)-amino]-3-(4′-trifluoromethyl-biphenyl-4-yl)-propionicacid (96 mg, 0.0.16 mmol), N-methyl piperazine (22 μL, 0.19 mmol), HBTU(68 mg, 0.18 mmol) and DIEA (43 μL, 0.24 mmol) similar to generalprocedure A. Silica gel chromatography using 25% EtOAc in hexanesafforded the title compound.

LC-MS (m/z): 670 (M+1)⁺; ¹H NMR (400 MHz, CDCl₃): δ 2.22 (s, 3H),2.30-2.36 (m, 4H), 3.13-3.21 (m, 2H), 3.42 (m, 2H), 3.62 (m, 2H), 3.82(s, 3H), 5.36 (q, 1H), 7.09 (d, 1H), 7.20 (t, 1H), 7.28 (d, 2H),7.39-7.42 (m, 1H), 7.46 (d, 3H), 7.57 (d, 1H), 7.59 (m, 2H), 7.63 (m,2H), 7.66 (m, 2H), and 12.14 (s, 1H).

Example 67 4-Hydroxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid[1-(3′-chloro-4′-fluoro-biphenyl-4-ylmethyl)-2-(S)-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-amide

4-Hydroxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid[1-(3′-chloro-4′-fluoro-biphenyl-4-ylmethyl)-2-(S)-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-amide(46 mg) was prepared from3-(3′-Chloro-4′-fluoro-biphenyl-4-yl)-2-(S)-[(4-hydroxy-4′-trifluoromethyl-biphenyl-3-carbonyl)-amino]-propionicacid (55 mg, 0.1 mmol) and N-methyl piperazine following the generalprocedure A.

LC-MS (m/z): 640 (M+1)⁺; ¹H NMR (400 MHz, CDCl₃): δ 2.22 (s, 3H),2.30-2.36 (m, 4H), 3.13-3.21 (m, 2H), 3.42 (m, 2H), 3.62 (m, 2H), 5.36(q, 1H), 7.09 (d, 1H), 7.20 (t, 1H), 7.28 (d, 2H), 7.39-7.42 (m, 1H),7.46 (d, 3H), 7.57 (d, 1H), 7.59 (m, 2H), 7.63 (m, 2H), 7.66 (m, 2H),and 12.14 (br, 1H).

Example 68 4-Hydroxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid{2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-[(2-dimethylamino-ethyl)-methyl-carbamoyl]-ethyl}-amide

4-Hydroxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid{2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-[(2-dimethylamino-ethyl)-methyl-carbamoyl]-ethyl}-amide(49 mg, 76%) was prepared from3-(3′-Chloro-4′-fluoro-biphenyl-4-yl)-2-(R)-[(4-hydroxy-4′-trifluoromethyl-biphenyl-3-carbonyl)-amino]-propionicacid (55 mg, 0.1 mmol) following the general procedure A.

LC-MS (m/z): 643 (M+3)⁺; ¹H NMR (400 MHz, CDCl₃): δ 2.02 (s, 3H), 2.12(s, 6H), 2.28 (m, 1H), 2.42 (m, 1H), 3.24 (t, 2H), 3.38 (m, 2H), 4.74(q, 1H), 7.10 (dd, 1H), 7.18 (t, 2H), 7.36 (m, 2H), 7.44 (dd, 2H), 7.49(d, 2H), 7.56 (m, 1H), 7.68 (d, 2H), 7.72 (d, 2H), 7.78 (t, 1H), and12.12 (br, 1H).

Example 69 4-Hydroxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid[1-(R)-(3′-chloro-4′-fluoro-biphenyl-4-ylmethyl)-2-oxo-propyl]-amide

4-Methoxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid[2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(methoxy-methyl-carbamoyl)-ethyl]-amide(0.13 g) was prepared from the3-(3′-Chloro-4′-fluoro-biphenyl-4-yl)-2-(R)-[(4-methoxy-4′-trifluoromethyl-biphenyl-3-carbonyl)-amino]-propionicacid (0.16 g, 0.28 mmol) and N,O-dimethylhydroxylamine hydrochloride(0.027, 0.28 mmol) according to the general procedure A.

To a solution of 4-Methoxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid[2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(methoxy-methyl-carbamoyl)-ethyl]-amide(0.1 g, 0.162 mmol) in anhydrous THF (2 mL) was added methyl magnesiumbromide [0.35 ml, 1.4M solution in Toluene/THF (75:25)] at 0° C. andallowed to come to room temperature and stirred for 6 h. Reaction wasquenched with aq NH₄Cl and extracted with EtOAc. Organic layer waswashed with water, brine and dried over Na₂SO₄. Solvent was removedunder reduced pressure and the residue was purified by silicagel columnchromatography to get pure4-Methoxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid[1-(R)-(3′-chloro-4′-fluoro-biphenyl-4-ylmethyl)-2-oxo-propyl]-amide(0.055 g)

LC/MS (m/z): 570.2 (M+1)⁺.

4-Hydroxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid[1-(R)-(3′-chloro4′-fluoro-biphenyl-4-ylmethyl)-2-oxo-propyl]-amide,example 73 (0.028 g) was prepared from4-Methoxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid[1-(R)-(3′-chloro-4′-fluoro-biphenyl-4-ylmethyl)-2-oxo-propyl]-amide(0.05 g, 0.087 mmol) following general procedure P. ¹HNMR (400 MHz,CDCl₃): 2.30 (s, 3H), 3.27 (dd, 1H), 3.37 (dd, 1H), 5.10 (s, 1H)7.08-7.30 (m, 5H) 7.38 (m, 1H), 7.44-7.52 (m, 3H), 7.54-7.70 (m, 6H),12.15 (s, 1H)

LC/MS (m/z): 556.9 (M+1)⁺.

Example 70 4-Hydroxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid[2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide

[2-(3′-Chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-carbamicacid tert-butyl ester (96 mg,) was prepared from2-(R)-tert-butoxycarbonylamino-3-(3′-chloro-4′-fluoro-biphenyl-4-yl)-propionicacid pentafluorophenyl ester (140 mg, 0.25 mmol) andN-hydroxy-acetamidine (37 mg, 0.5 mmol) following the general procedureO.

2-(3′-Chloro-4′-fluoro-biphenyl-4-yl)-1-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethylamine(33 mg) was prepared from[2-(3′-Chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-carbamicacid tert-butyl ester (43 mg, 0.1 mmol) and hydrochloric acid (0.5 mL,4.0 M. solution in dioxane) following the typical Boc deprotectionprocedure N.

4-Methoxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid[2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide(55 mg) was prepared from4-Methoxy-4′-trifluoromethyl-biphenyl-3-carbonyl chloride (31 mg, 0.1mmol) and2-(3′-Chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethylamine(40 mg, 0.12 mmol) following the general procedure M.

LC-MS (m/z): 610 (M+1)⁺; ¹H NMR (400 MHz, CDCl₃): δ 2.41 (s, 3H), 3.59(t, 2H), 3.91 (s, 3H), 5.87 (q, 1H), 7.08 (d, 1H), 7.20 (dd, 2H), 7.38(m, 1H), 7.46 (d, 3H), 7.58 (dd, 1H), 7.64-7.72 (m, 4H), 7.74 (d, 1H),7.82 (dd, 1H), and 12.16 (br, 1H).

4-Hydroxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid[2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide(94 mg) was prepared from4-methoxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid[2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide(122 mg, 0.20 mmol) and boron tribromide (0.5 mL, 0.5 mmol, 1.0 Msolution in DCM) following the general procedure P.

LC-MS (m/z): 596 (M+1)⁺; ¹H NMR (400 MHz, CDCl₃): δ 2.41 (s, 3H), 3.45(d, 2H), 3.98 (m, 1H), 5.84 (q, 1H), 6.98 (d, 1H), 7.10 (d, 1H),7.16-7.20 (m, 2H), 7.36 (m, 1H), 7.44 (d, 2H), 7.48 (d, 1H), 7.58 (m,2H), 7.62-7.68 (m, 4H), and 11.85 (br, 1H).

By analogous methods to those described above the following compoundswere synthesized. LC/MS EX. NAME (M + 1) 714-Hydroxy-4′-methanesulfonyl-biphenyl-3-carboxylic 631.7 acid[2-(4′-methanesulfonyl-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide 724-Hydroxy-3′,5′-bis-trifluoromethyl-biphenyl-3- 689.6 carboxylic acid[2-(4′-methanesulfonyl-biphenyl-4-yl)-1-(R)-(-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide 733′,4′-Difluoro-4-hydroxy-biphenyl-3-carboxylic acid 547.5[2-(3′,4′-difluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide 744-Hydroxy-4′-trifluoromethyl-biphenyl-3-carboxylic 611.5 acid[1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-2-(4′-trifluoromethyl-biphenyl-4-yl)-ethyl]-amide

Example 75 4-Hydroxy-3′,5′-bis-trifluoromethyl-biphenyl-3-carboxylicacid[2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide

4-Ethoxy-3′,5′-bis-trifluoromethyl-biphenyl-3-carboxylic acid[2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide(57 mg) was prepared from2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethylamine(33 mg, 0.10 mmol) and4-Ethoxy-3′,5′-bis-trifluoromethyl-biphenyl-3-carboxylic acid (37 mg,0.1 mmol) following the general procedure A.

LC-MS (m/z): 693 (M+2)⁺; ¹H NMR (400 MHz, CDCl₃): δ 1.49 (t, 3H), 2.41(s, 3H), 3.47 (d, 2H), 4.09 (q, 2H), 5.85 (q, 1H), 7.03 (d, 1H), 7.19(m, 2H), 7.38 (m, 1H), 7.42 (d, 4H), 7.52 (dd, 1H), 7.58 (d, 1H), 7.64(dd, 1H), 7.81 (s, 2H), and 7.88 (s, 1H).

4-Hydroxy-3′,5′-bis-trifluoromethyl-biphenyl-3-carboxylic acid[2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide(48 mg) was prepared from4-Ethoxy-3′,5′-bis-trifluoromethyl-biphenyl-3-carboxylic acid[2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide (69 mg, 0.10 mmol) and boron tribromide (0.25 mL, 0.25 mmol, 1.0 Msolution in DCM) following the general procedure P.

LC-MS (m/z): 665 (M+2)⁺; ¹H NMR (400 MHz, CDCl₃): δ 2.39 (s, 3H), 3.45(d, 2H), 5.84 (q, 1H), 7.08 (d, 1H), 7.18 (m, 2H), 7.38 (m, 1H), 7.44(d, 4H), 7.54 (dd, 1H). 7.60 (d, 1H), 7.66 (dd, 1H), 7.83 (s, 2H), 7.90(s, 1 H), and 11.91 (br, 1H).

Example 76 Acetic acid3-[2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethylcarbamoyl]-4′-trifluoromethyl-biphenyl-4-ylester

Acetic acid3-[2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethylcarbamoyl]-4′-trifluoromethyl-biphenyl-4-ylester (45 mg) was prepared from2-(3′-Chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethylamine(33 mg, 0.1 mmol) and acetic acid3-chlorocarbonyl-4′-trifluoromethyl-biphenyl-4-yl ester (34 mg, 0.1mmol) following the general procedure M.

LC-MS (m/z): 582 (M+2)⁺; ¹H NMR (400 MHz, CDCl₃): δ 2.10 (s, 3H), 2.39(s, 3H), 3.42 (dd, 1 H), 3.50 (dd, 1H), 5.85 (q, 1H), 7.06 (d, 1H), 7.24(dd, 2H), 7.38 (m, 1H), 7.42 (d, 2H), 7.48 (d, 1H), 7.58 (dd, 1H), 7.69(m, 4H), 7.74 (d, 2H), and 8.18 (d, 1H).

Example 77 4-Hydroxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid[2-(4′-benzyloxy-3′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide

4-Hydroxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid[(4′-benzyloxy-3′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide(58 mg) was prepared from acetic acid3-chlorocarbonyl-4′-trifluoromethyl-biphenyl-4-yl ester (1.96 mL, 0.1 MCH₂Cl₂),2-(4′-benzyloxy-3′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethylaminehydrochloride (90 mg, 0.178 mmol) and DIEA (95 μL, 0.55 mmol) analogousto procedure M. The crude reaction mixture was concentrated andredissolved in THF (3 mL) and MeOH (1 mL). 1N NaHCO₃ (200 μL) and 1 NNa₂CO₃ (50 μL) were added and the hydrolysis was followed by TLC andLCMS. Once complete, the reaction was diluted with EtOAc and the layerswere separated. After extraction and drying the combined organics overMgSO₄, the crude mixture was concentrated onto silica gel and purifiedby chromatography using 15% EtOAc in hexanes.

LC-MS (m/z): 668 (M+1)⁺; ¹H NMR (400 MHz, CDCl₃): δ 2.40 (s, 3H), 3.43(d, 2H), 5.20 (s, 2H), 5.82 (q, 1H), 7.02-7.22 (m, 5H), 7.27-7.41(m,2H), 7.42-7.44 (m, 6H), 7.50-7.68 (m, 6H), 11.83 (s, 1 H).

Example 78 4-Hydroxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid[2-(4′-methanesulfonyl-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide

4-Hydroxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid[2(4′-methanesulfonyl-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide(49 mg) was prepared from acetic acid3-chlorocarbonyl-4′-trifluoromethyl-biphenyl-4-yl ester (1.93 mL, 0.1 MCH₂Cl₂) and2-(4′-methanesulfonyl-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethylaminehydrochloride (80 mg, 0.175 mmol) and DIEA (92 μL, 0.525 mmol) usingstandard procedure M. The crude reaction mixture was concentrated andredissolved in THF (3 mL) and MeOH (1 mL). 1 N NaHCO₃ (200 μL) and 1NNa₂CO₃ (50 μL) were added and the hydrolysis was followed by TLC andLCMS. Once complete, the reaction was diluted with EtOAc and the layerswere separated. After extraction and drying the combined organics overMgSO₄, the crude mixture was concentrated onto silica gel and purifiedby chromatography using 15% EtOAc in hexanes.

LC-MS (m/z): 622 (M+1)⁺; ¹H NMR (400 MHz, CDCl₃): δ 2.42 (s, 3H), 3.09(s, 3H), 3.46 (d, 2H), 5.86 (q, 1H), 7.09-7.19 (m, 3H), 7.23 (d, 2H),7.52-7.73 (m, 8H), 7.99 (d, 2H), 11.80(s, 1H).

Example 79 4-Hydroxy-4′-nitro-biphenyl-3-carboxylic acid[2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide

4-Hydroxy-4′-nitro-biphenyl-3-carboxylic acid (1.98) was prepared from5-bromosalicylic acid (2.6 g, 11.9 mmol ) and 4-nitrophenylboronic acid(3.0 g, 17.9) following general procedure D

To a solution of 4-Hydroxy-4′-nitro-biphenyl-3-carboxylic acid (2.0 g,7.71 mmol) in acetone was added K₂CO₃(2.34 g, 16.9 mmol) and Mel (4.3 g,30.8 mmol) and refluxed for 12 h. Reaction mixture was diluted withEtOAc and filtered, filtrate was washed with water brine and dried overNa₂SO₄. Solvent was removed under reduced pressure and silicagel columnchromatography gave pure 4-Methoxy-4′-nitro-biphenyl-3-carboxylic acidmethyl ester (1.9 g).

To a solution of 4-Methoxy-4′-nitro-biphenyl-3-carboxylic acid methylester (0.15 g, 0.52 mmol) in THF-MeOH (3:1) was added LiOH (1.04 mL of1N solution) and heated at 65° C. for 12 h. Reaction mixture wasacidified with HCl (1N, 1.04 mL) and diluted with EtOAc, and washed withwater, brine and dried over Na₂SO₄. Solvent was removed under reducedpressure and the product 4-Methoxy-4′-nitro-biphenyl-3-carboxylic acid(0.12 g) was used in the next reaction without further purification.

4-Methoxy-4′-nitro-biphenyl-3-carboxylic acid[2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide(0.045 g) was prepared from 4-Methoxy-4′-nitro-biphenyl-3-carboxylicacid (0.03 g, 0.11 mmol) and2-(3′-Chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethylaminehydrochloride salt (0.04 g, 0.11 mmol) following general procedure A

LC/MS (m/z): 587.9 (M+1)⁺.

4-Hydroxy-4′-nitro-biphenyl-3-carboxylic acid[2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide(0.017 g) was prepared from 4-Methoxy-4′-nitro-biphenyl-3-carboxylicacid[2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide(0.03 g, 0.05 mmol) following general procedure P.

¹HNMR (400 MHz, CDCl₃): 2.42 (s, 3H), 3.46 (dd, 2H), 5.84 (m, 1H), 6.94(d, 1H), 7.10-7.24 (m, 4H), 7.38 (m, 1H), 7.45 (d, 2H), 7.51 (d, 1H),7.56 (dd, 1H), 7.64 (m 2H), 7.70 (m, 1H) 8.26 (d, 2H), 11.90 (s, 1H).

LC/MS (m/z): 573.8 (M+1)⁺.

Example 80 6-Benzyloxy-4-hydroxy4′-trifluoromethyl-biphenyl-3-carboxylicacid[2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide

To a solution of 5-Bromo-2,4-dihydroxy-benzoic acid methyl ester (1.0 g,4.04 mmol) in DMF (7 mL) was added Cs₂CO₃ (1.58 g, 4.85 mmol) andbenzylbromide (0.69 g, 4.04 mmol) and heated at 70° C. for 6 h. Reactionmixture was diluted with EtOAc (10 mL) and filtered, filtrate was washedwith water, brine and dried over Na₂SO₄. Solvent was removed underreduced pressure and silicagel column chromatography (EtOAc:Hex, 1:3)gave pure 4-benzyloxy-5-bromo-2-hydroxy-benzoic acid methyl ester (0.62g).

To a solution of 4-benzyloxy-5-bromo-2-hydroxy-benzoic acid methyl ester(0.5 g, 1.48 mmol) in toluene (5 mL) was added 4-trifluorophenylboronicacid (0.56 g, 2.96 mmol), tetrakistriphenylphosphine (0.17 g, 0.14mmol), Na₂CO₃(2.96 ml, 1N solution) and stirred the reaction mixture at80° C. for 12 h. Reaction mixture was diluted with EtOAc (10 mL) andwashed with water, brine and dried over Na₂SO₄. Solvent was removedunder reduced pressure and silicagel column chromatography (20:80EtOAc:hexane) gave pure6-Benzyloxy-4-hydroxy-4′-trifluoromethyl-biphenyl-3-carboxylic acidmethyl ester (0.39 g).

6-Benzyloxy-4-hydroxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid(0.13 g,) was prepared from6-Benzyloxy-4-hydroxy-4′-trifluoromethyl-biphenyl-3-carboxylic acidmethyl ester (0.16 g, 0.39 mmol) following general procedure C.

To a solution of6-Benzyloxy-4-hydroxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid (52mg, 0.13 mmol) in THF:DCE (1:1, 2 mL) was added PS-Carbodiimide resin(0.14 g, 1.3 mmol/g) and2-(3′-Chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethylamine(0.03 g, 0.09 mmol) and stirred for 12 h, resin was filtered and washedwith EtOAc (5 mL), filtrate was concentrated and silicagelchromatography of the residue gave pure6-Benzyloxy-4-hydroxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid[2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide(0.013 g).

¹HNMR (400 MHz, CDCl₃): 2.39 (s, 3H), 3.42 (dd, 2H), 5.13 (s, 2H), 5.80(m 1H), 6.63 (s, 1H), 6.68 (d, 1H), 7.10-7.24 (m, 4H), 7.27-7.40 (m,6H), 7.42 (d, 2H), 7.54-7.64 (m, 5H), 12.2 (s, 1H); LC/MS (m/z): 703.0(M+1)⁺.

Example 81 5-Chloro-4-hydroxy-4′-trifluoromethyl-biphenyl-3-carboxylicacid[2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide

N-Bromosuccinimide (2.38 g, 13.38 mmol) was added to a solution of3-chlorosalicylic acid (2.1 g, 12.16 mmol) in CH₃CN (10 mL) solution andstirred for 1 h, reaction mixture was diluted with water (25 mL), solidswere filtered and washed with water and dried to get5-Bromo-3-chloro-2-hydroxy-benzoic acid (2.87 g).

Methyl Iodide (3.83 g, 27.04 mmol) was added to a solution of5-Bromo-3-chloro-2-hydroxy-benzoic acid (1.7 g, 6.76 mmol) and Cs₂CO₃(4.83 g, 14.86 mmol) in DMF (10 mL) and heated at 50° C. for 12 h. Thereaction mixture was diluted with EtOAc (30 mL) and filtered over celitepad. Filtrate was washed with water, brine and dried over Na₂SO₄.Solvent was removed and the residue was purified by silicagel columnchromagography to get pure 5-Bromo-3-chloro-2-methoxy-benzoic acidmethyl ester (1.56 g).

4-Trifluoromethylphenylboronic acid (0.815 g, 4.29 mmol) was added to asolution of 5-Bromo-3-chloro-2-methoxy-benzoic acid methyl ester (1.0 g,3.57 mmol), Pd(PPh₃)₄ (0.2 g, 0.178 mmol) and CsF (1.08 g, 7.15 mmol) inDME (10 mL ) and heated at 85° C. for 10 h. The reaction was dilutedwith EtOAc (20 mL) and filtered, filtrate was washed water, brine anddried over Na₂SO₄. Solvent was removed under reduced pressure and thesilicagel column chromatography gave pure5-Chloro-4-methoxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid methylester (0.94 g).

5-Chloro-4-methoxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid (0.62g) was prepared from5-Chloro-4-methoxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid methylester (0.7 g, 2.03 mmol) following the procedure C.

5-Chloro-4-methoxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid[2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide(0.5 g) was prepared from5-Chloro-4-methoxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid (0.4 g,1.2 mmol) and2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethylamine(0.4 g, 1.2 mmol) according to the general procedure A.

LC/MS (m/z): 644.0 (M+1)⁺.

5-Chloro-4-hydroxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid[2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide(0.22 g) was prepared from5-Chloro-4-methoxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid[2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide(0.4 g, 0.62 mmol) following general procedure P.

¹HNMR (400MHz, CDCl₃): 2.41 (s, 3H), 3.46 (m, 2H), 5.83 (dd, 1H),7.06-7.23 (m, 4H), 7.35-7.70 (m, 10H), 7.77 (d, 1H)

LC/MS (m/z): 630.5 (M+1)⁺.

Example 82 Acetic acid5′-[2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)ethylcarbamoyl]-4-trifluoromethyl[1,1′;3′,1″]terphenyl-4′-yl ester

To a solution of5-Bromo-4-hydroxy-4′-trifluoromethyl-biphenyl-3-carboxylic acidmethylester (0.3 g, 0.8 mmol) in toluene (5 mL) was added phenylboronicacid (0.19 g, 1.6 mmol), tetrakistriphenylphosphine (0.0.09 g, 0.08mmol), Na₂CO₃(2.4 ml, 1N solution) and stirred the reaction mixture at80° C. for 10 h. The reaction mixture was diluted with EtOAc (10 mL) andwashed with water, brine and dried over Na₂SO₄. Solvent was removedunder reduced pressure and silicagel column chromatography (20:80EtOAc:hexane) gave pure4′-Hydroxy-4-trifluoromethyl-[1,1′;3′,1″]terphenyl-5′-carboxylic acidmethyl ester (0.21 g).

4′-Hydroxy-4-trifluoromethyl-[1,1′;3′,1″]terphenyl-5′-carboxylic acid(0.17 g) was prepared from 4′-Hydroxy-4-trifluoromethyl-[1,1′;3′,1″]terphenyl-5′-carboxylic acid methyl ester (0.2 g, 0.53 mmol )following general procedure C.

Acetic acid5′-[2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethylcarbamoyl]-4-trifluoromethyl-[1,1′;3′,1″]terphenyl-4′-yl ester (0.04 g ) was prepared from Acetic acid5′-chlorocarbonyl-4-trifluoromethyl-[1,1′;3′,1″]terphenyl-4′-yl ester(0.06 g, 0.14 mmol) [prepared from4′-Hydroxy-4-trifluoromethyl-[1,1′;3′,1″]terphenyl-5′-carboxylic acidfollowing general procedures K & L.] and2-(3′-Chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethylamine(0.047 g,0.14 mmol) following general procedure M.

¹HNMR (400 MHz, CDCl₃): 1.85 (s, 3H), 2.39 (s, 3H), 3.37 (dd, 1H), 3.53(dd, 1H), 5.84 (m, 1H), 7.09-7.24 (m, 4H), 7.33-7.50 (m, 8H), 7.55 (dd,1H), 7.64-7.73 (m, 5H), 7.99 (d, 1H), LC/MS (m/z): 744.9 (M+1)⁺.

Example 83 4-Hydroxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid[2-(4-benzyloxy-phenyl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide

[2-(4-Benzyloxy-phenyl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-carbamicacid tert-butyl ester (2.75 g) was prepared from N-boc-O-benzyl tyrosine(2.6 g, 7.00 mmol) following general procedure G.

2-(4-Benzyloxy-phenyl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethylaminehydrochloride salt (1.27 g) was prepared from the[2-(4-Benzyloxy-phenyl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-carbamicacid tert-butyl ester (1.5 g, 3.67 mmol) following general procedure N.

4-Hydroxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid[2-(4-benzyloxy-phenyl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amidewas prepared from Acetic acid3-chlorocarbonyl-4′-trifluoromethyl-biphenyl-4-yl ester (0.32 g, 0.93mmol) and2-(4-Benzyloxy-phenyl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethylaminehydrochloride salt (0.32 g, 0.93 mmol) following the general procedureM. followed by the hydrolysis of the resulting acetate using K₂CO₃.

¹HNMR (400 MHz, CDCl₃): 2.39 (s, 3H), 3.35 (d, 2H), 5.01 (s, 2H), 5.75(, 1H), 6.85-6.93 (m, 3H), 6.97-7.21(m, 2H), 7.10 (d, 1H), 7.29-7.43 (m,5H), 7.46 (d, 1H), 7.59 (d, 2H), 7.65 (dd, 1H), 7.70 (d, 2H).11.90 (s,1H)

Example 84 4-Hydroxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid[2-(4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide

4-Hydroxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid[2-(4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide(0.018) was prepared from4-Methoxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid[2-(4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl[1,2,4]oxadiazol-5-yl)-ethyl]-amide (0.03 g, 0.052 mmol) using thegeneral procedure P.

¹HNMR (400 MHz, CDCl₃): 2.41 (s, 3H), 3.46 (d, 2H), 5.82 (dd, 1H), 6.82(br d, 1H), 7.08-7.19 (m, 2H), 7.42 (s, 1H), 7.46-7.68 (m, 9H), 11.80(s, 1H)

Example 85 5-Fluoro-4-hydroxy-4′-trifluoromethyl-biphenyl-3-carboxylicacid[2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide

To a solution of 5-Bromo-3-fluoro-2-hydroxy-benzaldehyde (2.0 g, 9.13mmol), in DMF (10 mL) was added Cs₂CO₃ (3.56 g, 10.95 mmol) andiodomethane (2.59 g, 18.26 mmol) and heated at 70° C. for 6 h. Reactionmixture was diluted with EtOAc (25 mL) and filtered, filtrate was washedwith water, brine and dried over Na₂SO₄. Solvent was removed underreduced pressure and silicagel column chromatography (EtOAc:Hex, 1:3)gave pure 5-Bromo-3-fluoro-2-methoxy-benzaldehyde (2.0 g).

4-Trifluorophenylboronic acid (1.05 g, 5.57 mmol) was added to asolution of 5-Bromo-3-fluoro-2-methoxy-benzaldehyde (1.0 g, 4.29 mmol),Pd(PPh₃)₄ (0.24 g, 0.21 mmol) and CsF (1.3 g, 8.58 mmol) in DME (10 mL)and heated at 85° C. for 10 h. The reaction was diluted with EtOAc (20mL) and filtered, filtrate was washed water, brine and dried overNa2SO4. Solvent was removed under reduced pressure and the silicagelcolumn chromatography gave pure5-Fluoro-4-methoxy-4′-trifluoromethyl-biphenyl-3-carboxaldehyde (0.91g).

Pyridinium dichromate (0.25 g, 0.67 mmol ) was added to a solution of5-Fluoro-4-methoxy-4′-trifluoromethyl-biphenyl-3-carbaldehyde (0.2 g,0.67 mmol) DMF (2 mL) and stirred for 12 h, to complete the reactionmore pyridinium dichromate (0.2 g , 0.53 mmol) was added and stirred for12 h. The reaction mixture was diluted with water (5 mL) and extractedwith EtOAc(10 mL). Solvent was removed under reduced pressure to get5-Fluoro-4-methoxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid (0.12g).

5-Fluoro-4-methoxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid[2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amidewas prepared from5-Fluoro-4-methoxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid (0.06g, 0.19 mmol) and2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethylamine(0.063 g, 0.19 mmol) following general procedure A.

LC/MS (m/z): 628.0 (M+1)⁺.

5-Fluoro-4-hydroxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid[2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amidewas prepared from5-Fluoro-4-methoxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid[2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amidefollowing general procedure P.

¹HNMR (400 MHz, CDCl₃): 2.41 (s, 3H), 3.46 (m, 2H), 5.83 (dd, 1H), 7.00(br d, 1H), 7.12-7.23 (3H), 7.30 (s, 1H), 7.38 (m, 1H), 7.43-7.60 (m,6H), 7.66 (d, 2H).

Example 86 4-Hydroxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid[2-[4-(3-chloro-4-fluoro-phenoxy)-phenyl]-1-(R)-(3-methyl1,2,4]oxadiazol-5-yl)-ethyl]-amide

2-(R)-tert-Butoxycarbonylamino-3-[4-(3-chloro-4-fluoro-phenoxy)-phenyl]-propionicacid (0.87 g) was prepared from Boc-D-tyrosine methyl ester (1.0 g, 3.38mmol) 3-chloro-4-fluorophenylboronic acid (1.76 g, 10.15 mmol) asdescribed in the general procedure F.

[2-[4-(3-Chloro-4-fluoro-phenoxy)-phenyl]-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-carbamicacid tert-butyl ester (0.57 g ) was prepared from2-(R)-tert-Butoxycarbonylamino-3-[4-(3-chloro-4-fluoro-phenoxy)-phenyl]-propionicacid [0.73 g, 1.78 mmol, which was prepared from2-(R)-tert-Butoxycarbonylamino-3-[4-(3-chloro-4-fluoro-phenoxy)-phenyl]-propionicacid methyl ester using the general procedure C] following the generalprocedure O.

4-Methoxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid[2-[4-(3-chloro-4-fluoro-phenoxy)-phenyl]-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide(0.07 g) was prepared from2-[4-(3-Chloro-4-fluoro-phenoxy)-phenyl]-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethylaminehydrochloride [0.07 g, 0.182 mmol, which was prepared from[2-[4-(3-Chloro-4-fluoro-phenoxy)-phenyl]-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-carbamicacid tert-butyl ester following general procedure N] and4-methoxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid (0.053 g, 0.18mmol) following general procedure A.

4-Hydroxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid[2-[4-(3-chloro-4-fluoro-phenoxy)-phenyl]-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide(0.022 g) was prepared from4-methoxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid[2-[4-(3-chloro-4-fluoro-phenoxy)-phenyl]-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide(0.04 g, 0.063 mmol) following general procedure P. ¹HNMR (400 MHz,CDCl₃): 2.40 (s, 3H), 3.39 (m, 2H), 5.78 (dd, 1H), 6.80-6.94 (m, 4H),6.90-7.14 (m, 5H), 7.47 (s, 1H), 7.54-7.74 (m, 5H), 11.85 (s, 1H); LC/MS(m/z): (M+1)⁺.

Example 87 4-Hydroxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid[2-(3′-chloro-4′-fluoro-biphenyl-3-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide

2-(R)-tert-Butoxycarbonylamino-3-(3′-chloro-4′-fluoro-biphenyl-3-yl)-propionicacid (0.93 g) was prepared from (R)-N-Boc-3-bromophenylalanine (1.0 g,2.9 mmol) and 3-chloro-4-fluorophenylboronic acid (1.0 g, 5.8 mmol)following general procedure D.

[2-(3′-Chloro-4′-fluoro-biphenyl-3-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-carbamicacid tert-butylester (0.7 g) was prepared from2-(R)-tert-Butoxycarbonylamino-3-(3′-chloro-4′-fluoro-biphenyl-3-yl)-propionicacid (0.9 g, 2.2 mmol) following general procedure O.

4-Methoxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid[2-(3′-chloro-4′-fluoro-biphenyl-3-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide(0.073 g) was prepared from2-(3′-Chloro-4′-fluoro-biphenyl-3-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethylaminehydrochloride salt [0.07 g, 0.19 mmol, prepared from[2-(3′-Chloro-4′-fluoro-biphenyl-3-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-carbamicacid tert-butylester following general procedure N] and4-Methoxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid (0.056 g, 0.19mmol) following general procedure A.

4-Hydroxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid[2-(3′-chloro-4′-fluoro-biphenyl-3-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide(0.022 g) was prepared from4-Methoxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid[2-(3′-chloro-4′-fluoro-biphenyl-3-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide(0.04g, 0.065 mmol) following general procedure P.

¹HNMR (400 MHz, CDCl₃): 2.41 (s, 3H), 3.47 (m, 1H), 4.86 (m, 1H), 6.90(d, 1H), 7.07-7.15 (m, 4H), 7.20 (m, 1H), 7.29 (m, 1H), 7.37 (t, 1H),7.42-7.46 (m, 3H), 7.52 (d, 2H), 7.66 (d, 3H)11.81 (s, 1H)

Example 88 4-Hydroxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid[2-(3′-chloro-4′-fluoro-biphenyl-2-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide

[2-(3′-Chloro-4′-fluoro-biphenyl-2-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-carbamicacid tert-butylester (0.72 g) was prepared following general procedure Ofrom2-(R)-tert-Butoxycarbonylamino-2-(3′-chloro-4′-fluoro-biphenyl-2-yl)-propionicacid (1.0 g, 2.54 mmol) which was prepared from(D)-N-Boc-2-bromophenylalanine and 3-chloro-4-fluoro boronic acid,following general procedure D.

4-Methoxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid[2-(3′-chloro-4′-fluoro-biphenyl-2-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide(0.081 g) was prepared from2-(3′-Chloro-4′-fluoro-biphenyl-2-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethylaminehydrochloride salt (0.075 g, 0.2 mmol) which was prepared from2-(R)-tert-Butoxycarbonylamino-2-(3′-chloro-4′-fluoro-biphenyl-2-yl)-propionicacid following general procedure N and4-methoxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid (0.06 g, 0.2mmol) following general procedure A.

4-Hydroxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid[2-(3′-chloro-4′-fluoro-biphenyl-2-yI)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide(0.024) was prepared from4-Methoxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid[2-(3′-chloro-4′-fluoro-biphenyl-2-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide(0.04 g, 0.065 mmol) following general procedure P.

¹HNMR (400MHz, CDCl₃): 2.36 (s, 3H), 3.38 (dd, 1H), 3.47 (dd, 1H), 5.56(dd, 1H), 6.74 (d, 1H), 7.04 (m, 3H), 7.14-7.37 (m, 5H), 7.40 (d, 1H),7.60 (d, 2H), 7.66 (dd, 1H), 7.72 (d, 2H), 11.89 (s, 1H)

Example 895-Bromo-N-[2-(3′-chloro4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-ylethyl]-2-hydroxy-benzamide

The title compound (39 mg) was prepared from2-(3′-Chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethylamine(33 mg, 0.1 mmol) and 5-bromo-2-hydroxy-benzoic acid (21 mg, 0.1 mmol)following the general procedure A.

LC-MS (m/z): 532 (M+2)⁺; ¹H NMR (400 MHz, CDCl₃): δ 2.41 (s, 3H), 3.42(t, 2H), 5.79 (q, 1H), 6.82 (d, 1H), 6.90 (dd, 1H), 7.14 (d, 2H), 7.19(t, 2H), 7.40 (m, 1H), 7.48 (m, 2H), 7.52 (dd, 1H), 7.58 (dd, 1H), and11.82 (br, 1H).

Example 90 4-Hydroxy-3′,5′-bis-trifluoromethyl-biphenyl-3-carboxylicacid[2-biphenyl-4-yl-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide

4-Hydroxy-3′,5′-bis-trifluoromethyl-biphenyl-3-carboxylic acid[2-biphenyl-4-yl-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide (53mg) was prepared from4-benzyloxy-3′,5′-bis-trifluoromethyl-biphenyl-3-carboxylic acid[2-biphenyl-4-yl-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide (70mg, 0.1 mmol) and boron tribromide (0.25 mL, 0.25 mmol, 1.0 M solutionin DCM) following the general procedure P.

LC-MS (m/z): 613 (M+2)⁺; ¹H NMR (400 MHz, CDCl₃): δ 2.39 (s, 3H), 3.45(d, 2H), 5.85 (q, 1H), 7.11 (dd, 1H), 7.17 (d, 2H), 7.34 (d, 1H), 7.38(s, 1H), 7.41 (m, 2H), 7.49-7.53 (m, 3H), 7.56 (d, 1H), 7.63 (t, 1H),7.67 (t, 1H), 7.83 (s, 1H), 7.91 (m, 2H), and 11.94 (br, 1H).

Example 91 Acetic acid3-[2-(6-methoxy-4′-nitro-biphenyl-3-yl)-ethylcarbamoyl]-naphthalen-2-ylester

3-Acetoxy-naphthalene-2-carboxylic acid (232 mg) was prepared from3-hydroxy-naphthalene-2-carboxylic acid (188 mg, 1.0 mmol) following thegeneral procedure K.

Acetic acid3-[2-(6-methoxy-4′-nitro-biphenyl-3-yl)-ethylcarbamoyl]-naphthalen-2-ylester (108 mg) was prepared from 3-Acetoxy-naphthalene-2-carboxylic acid(58 mg, 0.25 mmol) and 2-(6-Methoxy-4′-nitro-biphenyl-3-yl)-ethylamine(68 mg, 0.25 mmol following the general procedure A.

LC-MS (m/z): 485 (M+1)⁺; ¹H NMR (400 MHz, CDCl₃): δ 2.25 (s, 3H), 2.95(t, 2H), 3.74 (q, 2H), 3.82 (s, 3H), 6.36 (br, 1H), 6.98 (d, 1H),7.22-7.32 (m, 2H), 7.46-7.58 (m, 4H), 7.66 (d, 2H), 7.82 (d, 2H), 8.14(s, 1H), and 8.24 (d, 1H).

Example 923-Biphenyl-4-yl-2-(S)-[(3-hydroxy-naphthalene-2-carbonyl)-amino]-propionicacid methyl ester

The title compound (26 mg) was prepared from 0.05 g (0.1 mmol) ofresin-bound 3-(4-bromophenyl)ethyl-(2g)-[3-(hydroxy-napthalene-2-carbonyl)-amino]-propionic acid methyl esterand 36.0 mg (0.3 mmol) of phenyl boronic acid as described in thegeneral procedure D followed by the cleavage described in example 28.LC/MS (m/z): 426 (M+1)⁺.

Example 933-(3′-Chloro-4′-fluoro-biphenyl-4-yl)-2-(S)-[(3-hydroxy-naphthalene-2-carbonyl)-amino]-propionicacid methyl ester

To 1.0 g (2.5 mmol) of resin-bound naphthoic acid obtained using theprocedure described in example 1, was added 1.95 g (7.5 mmol) of(S)-4-bromophenylalanine methyl ester, 7.5 mL (7.5 mmol) of 1.0 M DIC inDMF, 7.5 mL (7.5 mmol) of 1.0 M HOBt in DMF, and a catalytic amount ofDMAP. The resulting mixture was left on a shaker overnight. The resinwas washed with DMF, MeOH, DCM three times of each to give resin-bound3-(4-bromophenyl)ethyl-2-(S)-[3-(hydroxy-napthalene-2-carbonyl)amino]-propionic acidmethyl ester.

To 0.05 g (0.1 mmol) of the above resin-bound3-(4-bromophenyl)ethyl-(2S)-[3-(hydroxy-napthalene-2-carbonyl)-amino]-propionicacid methyl ester in 2.0 mL of DME were added 52.0 mg (0.3 mmol) of3-chloro-4-fluorophenylboronic acid, 30 mg (0.03 mmol) of Pd(PPh₃)₄, and0.3 mL (0.6 mmol) of 2N Na₂CO₃ solution. The mixture was heated to 80°C. for 12 h. The resin was washed with H₂0, DMF, MeOH, DCM three timesof each and cleaved with TMSBr/TFA/DCM (1:1:5) at rt for 4 h. Theresidue obtained after removing the solvent was purified bychromatography (DCM) to give the title compound (30 mg). LC/MS (m/z) 478(M+1)⁺.

By analogous methods to those described above the following compoundswere synthesized. LC/MS EX. NAME (m/z)  943-(4′-Fluoro-biphenyl-4-yl)-2-(S)-[(3-hydroxy-naphthalene-2- 444carbonyl)-amino]-propionic acid methyl ester  953-(3′,4′-Difluoro-biphenyl-4-yl)-2-(S)- 462[(3-hydroxy-naphthalene-2-carbonyl)-amino]-propionic acid methyl ester 96 3-(4′-Chloro-biphenyl-4-yl)-2-(S)-[(3-hydroxy-naphthalene-2- 460carbonyl)-amino]-propionic acid methyl ester  972-(S)-[(3-Hydroxy-naphthalene-2-carbonyl)-amino]-3-(4′- 510trifluoromethoxy-biphenyl-4-yl)-propionic acid methyl ester  982-(S)-[(3-Hydroxy-naphthalene-2-carbonyl)-amino]-3-(4′- 493trifluoromethyl-biphenyl-4-yl)-propionic acid methyl ester  993-(3′,5′-Bis-trifluoromethyl-biphenyl-4-yl)-2-(S)-[(3-hydroxy- 562naphthalene-2-carbonyl)-amino]-propionic acid methyl ester 1003-(3′,5′-Difluoro-biphenyl-4-yl)-2-(S)- 462[(3-hydroxy-naphthalene-2-carbonyl)-amino]-propionic acid methyl ester101 2-(S)-[(3-Hydroxy-naphthalene-2-carbonyl)-amino]-3- 502[1,1′;4′,1″]terphenyl-4-yl-propionic acid methyl ester 1023-(2′-Fluoro-[1,1′;4′,1″]terphenyl- 5074″-yl)-2-(S)-[(3-hydroxy-naphthalene-2-carbonyl)-amino]- propionic acidmethyl ester 1033-(4′-tert-Butyl-biphenyl-4-yl)-2-[(3-hydroxy-naphthalene-2-(S)- 482carbonyl)-amino]-propionic acid methyl ester 1042-(S)-[(3-Hydroxy-naphthalene-2-carbonyl)-amino]-3-(4- 476naphthalen-2-yl-phenyl)-propionic acid methyl ester

Example 1052-(S)-[(3-Hydroxy-naphthalene-2-carbonyl)-amino]-3-(4-naphthalen-2-ylphenyl)-propionicacid methyl ester

To 1.0 g (2.5 mmol) of resin-bound naphthoic acid obtained using theprocedure described in example 1, was added 1.95 g (7.5 mmol) of(S)-4-hydroxyphenylalanine methyl ester, 7.5 mL (7.5 mmol) of 1.0 M DICin DMF, 7.5 mL (7.5 mmol) of 1.0 M HOBt in DMF, and a catalytic amountof DMAP. The resulting mixture was left on a shaker overnight. The resinwas washed with DMF, MeOH, DCM three times of each to give resin-bound2-(3-Hydroxy-naphthalene-2-carbonyl)-amino-3-(4-hydroxy-phenyl)-propionicacid methyl ester.

To 0.05 g (0.1 mmol) of resin-bound2-(S)-(3-Hydroxy-naphthalene-2-carbonyl)-amino-3-(4-hydroxy-phenyl)-propionicacid methyl ester was reacted with 2-(4-chloro-phenyl)-ethanol (156 mg,1.0 mmol), DIAD (1.0 mmol), Ph₃P (1.0 mmol) in THF at rt overnight.

The resin was washed and cleaved as described in Example 28 to give thetitle compound (25 mg). LC/MS (m/z) 504 (M+1)⁺.

Example 1063-{4-[2-(4-Chloro-phenyl)-ethoxy]-phenyl}-2-(S)-[(3-hydroxy-naphthalene-2-carbonyl)-amino]-propionicacid methyl ester

0.05 g (0.1 mmol) of resin-bound2-(S)-(3-Hydroxy-naphthalene-2-carbonyl)-amino-3-(4-hydroxy-phenyl)-propionicacid methyl ester obtained in Example 105 was reacted with2-(4-chloro-phenyl)-ethanol (156 mg, 1.0 mmol), DIAD (1.0 mmol), Ph₃P(1.0 mmol) in THF at rt overnight. The resulting resin was hydrolyzedaccording to general procedure C. The resin was then washed and cleavedas described in Example 28 to give the title compound (20 mg). LC/MS(m/z) 490 (M+1)⁺.

Example 1072-(S)-[(3-Hydroxy-naphthalene-2-carbonyl)-amino]-3-[4-(4-nitro-phenoxy)-phenyl]propionicacid methyl ester

To 0.05 g (0.1 mmol) of the above resin-bound2-(S)-(3-Hydroxy-naphthalene-2-carbonyl)-amino-3-phenyl-propionic acidmethyl ester as obtained in Example 105 was reacted with4-nitro-fluorobenzene (42 mg, 0.30 mmol) as described in generalprocedure B.

The resin was washed with H₂O, DMF, MeOH, DCM three times of each andcleaved with TMSBr/TFA/DCM (1:1:5) at rt for 4 h. The residue obtainedafter removing the solvent was purified by chromatography (DCM) to givethe title compound (28 mg). LC/MS (m/z) 487 (M+1)⁺.

Example 1082-(S)-[(3-Hydroxy-naphthalene-2-carbonyl)-amino]-3-[4-(3-phenyl-propylamino)-phenyl]-propionicacid methyl ester

400 mg (1.0 mmol) of resin-bound naphthoic acid was reacted with 560 mg(2.5 mmol) of (2S)-Amino-3-(4-nitro-phenyl)-propionic acid methyl esteras described in Example 105 to give resin-bound2-(S)-(3-Hydroxy-naphthalene-2-carbonyl)-amino-3-(4-nitro-phenyl)-propionicacid methyl ester.

To 0.10 g (0.2 mmol) of the above resin was reduced by excess SnCl₂hydrate in NMP at RT for 6 h, then reacted with 3-phenyl-propionaldehyde(134 mg, 1.0 mmol) as described in general procedure R. The resin wasthen washed and cleaved as described in Example 28 to give the titlecompound (48 mg). LC/MS (m/z) 483 (M+1)⁺.

Example 109[2-(S)-[(3-Hydroxy-naphthalene-2-carbonyl)-amino]-3-(4′-trifluoromethyl-biphenyl-4-yl)-propionylamino]-aceticacid methyl ester

The resin-bound(2S)-[(3-Hydroxy-napthalene-2-carbonyl)-amino]-3-[(4′-trifluoromethyl)-biphenyl-4-yl]-propionylamino]-aceticacid methyl ester (29 mg) was prepared from 0.05 g (0.1 mmol) ofresin-bound3-(4-bromophenyl)ethyl-(2S)-[3-(hydroxy-napthalene-2-carbonyl)-amino]-propionicacid methyl ester and 58.0 mg (0.3 mmol) of4-(trifluoromethyl)phenylboronic acid as described in general procedureD LC/MS (m/z): 494 (M+1)⁺.

The above methyl ester (100 mg, 0.1 mmol) was hydrolyzed according togeneral procedure C to afford the resin-bound(2S)-[(3-Hydroxy-napthalene-2-carbonyl)-amino]-3-[(4′-trifluoromethyl)-biphenyl-4-yl]-propionylamino]-aceticacid, which was reacted with glycine methyl ester (46 mg, 0.5 mmol) asdescribed in general procedure A. The resin was cleaved withTMSBr/TFA/DCM (1:1:5) at rt for 4 h. The residue obtained after removingthe solvent was purified by chromatography (DCM) to give the titlecompound (20 mg). LC/MS (m/z) 551 (M+1)⁺.

Example 110 3-Hydroxy-naphthalene-2-carboxylic acid[2-(4-methoxy-4′-nitro-biphenyl-3-yl)-ethyl]-amide

To 1.0 g (2.5 mmol) of resin-bound 3-hydroxy-2-naphthoic acid obtainedusing the procedure described in example 1, was added a mixture of 1.5 g(7.5 mmol) of 3-Bromo-6-methoxyphenethylamine, 7.5 mL (7.5 mmol) of 1.0M DIC in DMF, 7.5 mL (7.5 mmol) of 1.0 M HOBt in DMF, and a catalyticamount of DMAP. The resulting mixture was left on a shaker overnight.The resin was washed with DMF, MeOH, DCM three times of each to giveresin-bound N-2-(3-bromo-6-methoxyphenyl)ethyl-3-hydroxyl-2-naphthamide.

To 0.05 g (0.1 mmol) of above resin-boundN-2-(3-bromo-6-methoxyphenyl)ethyl-3-hydroxyl-2-naphthamide in 2.0 mL ofDME were added 36.6 mg (0.3 mmol) of 4-nitrophenylboronic acid, 30 mg(0.03 mmol) of Pd(PPh₃)₄, and 0.3 mL (0.6 mmol) of 2N Na₂CO₃ solution.The mixture was heated to 80° C. for 12 h. The resin was washed withH₂O, DMF, MeOH, DCM three times of each and cleaved with TMSBr/TFA/DCM(1:1:5) at rt for 4 h. The residue obtained after removing the solventwas purified by chromatography (100% methylene chloride) to give 22 mgof the title compound.

¹H NMR (400 MHz, CDCl₃): 2.99 (t, 2H), 3.77 (dd, 2H), 3.83 (s, 3H), 6.62(broad, 1H), 6.99 (d, 1H), 7.21 (s, 1H), 7.31-7.27 (m, 3H), 7.48 (t,1H), 7.69-7.61 (m, 4H), 7.81 (s, 1H), 8.20 (d, 2H); LC/MS (m/z):443(M+1)⁺.

Example 111 3-Hydroxy-naphthalene-2-carboxylic acid[2-(6-methoxy-4′-nitro-biphenyl-3-yl)-ethyl]-amide

The title compound (27 mg) was prepared from 0.05 g (0.1 mmol) ofresin-bound N-2-(3-bromo-4-methoxyphenyl)ethyl-3-hydroxyl-2-naphthamideand 50.0 mg (0.3 mmol) of 4-nitro-phenyl boronic acid as described inExample 110.

¹H NMR (400 MHz, CDCl₃): 3.11 (t, 2H), 3.78 (dd, 2H), 3.98 (s, 3H), 6.95(broad, 1H), 7.03 (d, 1H), 7.29 (d, 2H), 7.49-7.44 (m, 2H), 7.54 (dd,1H), 7.69-7.61 (m, 4H), 7.81 (s, 1H), 8.22 (d, 2H); LC/MS (m/z): 443(M+1)⁺.

Examples 112 and 113 3-Hydroxy-naphthalene-2-carboxylic acid[2-(4′-methanesulfonyl-4-methoxy-biphenyl-3-yl)-ethyl]-amide and3-Hydroxy-naphthalene-2-carboxylic acid[2-(4-hydroxy-4′-methanesulfonyl-biphenyl-3-yl)-ethyl]-amide

3-Methoxy-2-naphthoic acid 1 g, (4.95 mmol) and2-Methoxy-5-bromo-1-phenethylamine were coupled using the generalprocedure A, to obtain 450 mg of the coupled product.

The bromo derivative (414 mg, 1 mmol) was subjected to Sujuki couplingusing 4-Methylsulfonyl-1 phenylboronic acid 300 mg(1.5 mmol) using thegeneral procedure D which afforded 300 mg of the3-Methoxy-naphthalene-2-carboxylic acid[2-(4′-methanesulfonyl-4-methoxy-biphenyl-3-yl)-ethyl]-amide.

The above methyl ether (250 mg) was then hydrolyzed with BBr₃ followingthe general procedure P which was purified on silica gel column toafford the 3-Hydroxy-naphthalene-2-carboxylic acid[2-(4′-methanesulfonyl-4-methoxy-biphenyl-3-yl)-ethyl]-amide 10 mg aswell as the 3-Hydroxy-naphthalene-2-carboxylic acid[2-(4-hydroxy-4′-methanesulfonyl-biphenyl-3-yl)-ethyl]-amide (25 mg).

LC/MS 476 (M+1); ¹H NMR (400 MHz, CDCl₃): δ 3.05 (s, 3H), 3.1(m, 2H),3.75 (m, 2H), 3.85 (s, 3H), 7.0 (d, 1H), 7.25 (s, 1H), 7.5 (m, 3H), 7.62(d, 1H), 7.7 (m, 2H), 7.8 (m, 3H), 7.86 (d, 2H), 8.1 (d, 1H).

3-Hydroxy-naphthalene-2-carboxylic acid[2-(4-hydroxy-4′-methanesulfonyl-biphenyl-3-yl)-ethyl]-amide (Example113)

LC/MS 462 (M+1); ¹H NMR (400 MHz, CDCl₃): δ 3.1 (s, 3H), 3.15(m, 2H),3.7 (m, 2H), 7.0 (d, 1H), 7.2 (m, 1H), 7.3 (s, 1H), 7.5 (m, 5H), 7.7 (m,4H), 7.86 (d, 2H).

Example 114(3-{2-[(3-Hydroxy-naphthalene-2-carbonyl)-amino]-ethyl}-4′-methanesulfonyl-biphenyl-4-yloxy)-aceticacid methyl ester

To a solution of the 3-Hydroxy-naphthalene-2-carboxylic acid[2-(4-hydroxy-4′-methanesulfonyl-biphenyl-3-yl)-ethyl]-amide (18 mg,0.039 mmol) was in DMF were added ethylbromoacetate (0.039 mmol) andCs₂CO₃ (0.039 mmol, 13 mg). The reaction mixture was for 12 hr and thereaction mixture was diluted with ethylacetate and washed with water.The organic layer was separated, dried and the crude obtained afterremoval of the solvent was purified on a silicagel column to afford thedesired product 5 mg, and 5 mg of bis ester.

LC/MS 548 (M+1); ¹H NMR (400 MHz, CDCl₃): δ 1.37(t, 3H), 3.05(s, 3H),3.1(m, 2H), 3.65(m, 2H), 4.38(q, 2H), 4.82(s, 2H), 7.05(d, 1H), 7.15(s,1H), 7.35 (s, 1H), 7.45 (m, 2H), 7.55 (m, 1H), 7.7 (m, 3H), 7.95(m, 3H),8.9(s, 1H), 9.45(s, 1H), 9.5 (t, 1H).

Example 115 3-Hydroxy-naphthalene-2-carboxylic acid[2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide

3-Methoxy-2-naphthoic acid 86 mg (0.43 mmol) and the2-(3′-Chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethylamine100 mg (0.35 mmol) were coupled using the general procedure A. to affordthe 3-Methoxy-naphthalene-2-carboxylic acid[2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide60 mg.

The resulting methyl ether was hydrolysed using BBr₃ following thegeneral procedure P and provided the title compound (15 mg).

¹H NMR (400 MHz, CDCl₃): δ 2.4(s, 3H), 3.45(d, 2H), 5.9(m, 1H), 7.05(d,1H), 7.2(m, 3H), 7.3(m, 2H), 7.4(m, 2H), 7.5(m, 2H), 7.6(d, 1H), 7.7 (d,1 H), 7.75(d, 1H), 7.95(s, 1H), 11.15(s, 1H).

Example 1162-(S)-[5-Bromo-2-(2-morpholin-4-yl-ethoxy)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionicacid methyl ester

A solution of(2S)-(5-bromo-2-hydroxy-benzoylamino)-3-(2′-phenoxy-biphenyl-4-yl)-propionicacid methyl ester (25 mg, 46 μmol, obtained by following similarprocedure described for example 34), 2-morpholin-4-yl-ethanol (1.5 eq.,8.3 μL, 69 μmol) and triphenylphosphine (1.5 eq., 18 mg, 69 μmol) inanhydrous THF (1 mL) was treated with DIAD (1.5 eq., 13.5 μl, 69 μmol)as described in Procedure I. Flash column chromatography (4:1hexanes:EtOAc) provided 13 mg of the title compound. LCMS forC₃₅H₃₅BrN₂O₆: 659, 661.

By analogous methods to those described above, the following compoundswere synthesized. LC/MS M⁺, and EX. NAME M + 2 (m/z) 1172-(S)-[5-Bromo-2-(3-pyridin-4-yl-propoxy)- 665, 667benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)- propionic acid methyl ester118 2-(S)-{5-Bromo-2-[2-(2-oxo-pyrrolidin-1- 657, 659yl)-ethoxy]-benzoylamino}-3-(2′-phenoxy- biphenyl-4-yl)-propionic acidmethyl ester 119 2-(S)-[5-Bromo-2-(2-morpholin-4-yl-ethoxy)- 642 644 benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)- propionic acid methyl ester120 2-(S)-[5-Bromo-2-(4,4,4-trifluoro-butoxy)- 643, 645benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)- propionic acid 1212-(S)-[5-Bromo-2-(2-pyrrolidin-1-yl-ethoxy)- 657, 659benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)- propionic acid methyl ester

Example 1222-(S)-[(4-Butoxy-3′-chloro-4′-fluoro-biphenyl-3-carbonyl)-amino]-3-(3′-trifluoromethyl-biphenyl-4-yl)-propionic acid

A mixture of 5-bromo-2-hydroxy-benzoic acid (2.21 g, 10 mmol), butylbromide (3.46 g, 25 mmol), potassium carbonate (2.76 g, 20 mmol) and DMF(20 mL) was heated at 100° C. for 1 h. The reaction mixture waspartitioned between ether (120 mL) and brine (100 mL). Ether layer wasseparated and washed again with brine (100 mL), dried over MgSO₄.Purification by flash chromatography (ethyl acetate/hexanes 1:99, 1:19,1:9) gave 5-Bromo-2-butoxy-benzoic acid butyl ester as yellow oil (1.648g, 5.01 mmol).

The 4-Butoxy-3′-chloro-4′-fluoro-biphenyl-3-carboxylic acid butyl esterwas prepared following General Procedure D using5-bromo-2-butoxy-benzoic acid butyl ester (1.648 g, 5.01 mmol),3-chloro-4-fluoro-benzene boronic acid (1.31 g, 7.5 mmol), palladiumtetrakis-triphenylphosphine (0.289 g, 0.25 mmol), and Na₂CO₃(aq) (2.0 N,10 mL, 20 mmol) in DME (20 mL). The mixture was heated at 80° C. for 14h. Purification by flash chromatography (ethyl acetate/hexanes 1:19,1:9) gave the desired compound as yellow oil (0.966 g, 2.55 mmol).

Hydrolysis of the ester using General Procedure C (LiOH(1.87 g, 25mmol), THF (8 mL) and H₂O (2 mL). heated to 50° C. for 12 h furnishedthe acid as yellow solid which was used in the next step withoutpurification.

The3-(4-Bromo-phenyl)-2-(S)-[(4-Butoxy-3′-chloro-4′-fluoro-biphenyl-3-carbonyl)-amino]-propionicacid methyl ester was prepared following General Procedure A using4-butoxy-3′-chloro-4′-fluoro-biphenyl-3-carboxylic acid from previousstep, 2-(S)-amino-3-(4-bromo-phenyl)-propionic acid methyl esterhydrochloride salt (0.811 g, 2.75 mmol), HBTU (1.39 g,3.6 mmol) and DIEA(1.32 mL,7.5 mmol) in DMF (15 mL). Purification by flash chromatography(ethyl acetate/hexanes 1:7, 1:4) gave the title compound as colorlesssolid (0.677 g, 1.19 mmol).

2-(S)-[(4-Butoxy-3′-chloro-4′-fluoro-biphenyl-3-carbonyl)-amino]-3-(3′-trifluoromethyl-biphenyl-4-yl)-propionicacid methyl ester was prepared following General Procedure D using3-(4-bromo-phenyl)-2-(S)-[(4-Butoxy-3′-chloro-4′-fluoro-biphenyl-3-carbonyl)-amino]-propionicacid methyl ester ((0.677 g, 1.19 mmol), 3-trifluoromethyl-benzeneboronic acid (0.349 g, 1.8 mmol), palladium tetrakis-triphenylphosphine(69 mg, 0.06 mmol), and Na₂CO₃(aq) (2.0 N, 5 mL, 10 mmol) in DME (10mL). The mixture was heated at 76° C. for 19 h. Purification by flashchromatography (ethyl acetate/hexanes 1:5, 1:4) gave the methyl ester ofthe title compound (177 mg, 0.28 mmol).

The title compound was obtained as a white solid (70 mg, 0.114 mmol)from-2-(S)-[(4-butoxy-3′-chloro-4′-fluoro-biphenyl-3-carbonyl)-amino]-3-(3′-trifluoromethyl-biphenyl-4-yl)-propionicacid methyl ester (92 mg, 0.146 mmol), LiOH(aq) (2.0 N, 0.25 mL, 0.50mmol), THF (1 mL) and MeOH (0.25 mL) following the general Procedure C.

¹H-NMR (400 MHz, DMSO-d₆): 13.15(b, 1H), 8.59(d, 1H), 8.12(d, 1H),7.81-7.97(m, 4H), 7.63-7.73(m, 5H), 7.49(t, 1H), 7.24-7.31(m, 3H),4.89(m, 1 H), 4.09(m, 2H), 3.30(dd, 1H), 3.18(dd, 1H), 1.53(quin, 2H),1.19(m, 2H), 0.71(t, 3H); LC-MS m/z: 614 (M+1)⁺.

Example 1232-(S)-(5-Chloro-2-heptyloxy-benzoylamino)-3-(4′-trifluoromethoxy-biphenyl-4-yl)-propionicacid

5-Chloro-2-hydroxy-benzoic acid (2.5 g, 28.97 mmol) was coupled with2-Amino-3-(4-bromo-phenyl)-propionic acid methyl ester hydrochloride(4.26 g, 28.96 mmol) with HBTU (6.59 gms, 34.76 mmol) anddiisopropylethylamine (8 ml, 86.91 mmol) as per general procedure A toyield the3-(4-Bromo-phenyl)-(2S)-(5-chloro-2-hydroxy-benzoylamino)-propionic acidmethyl ester. The above hydroxy compound (0.500 g, 1.21 g) was thenalkylated with heptyliodide (0.410 g, 1.815 mmol) and potassiumcarbonate (0.050 g, 3.025 mmol) as per general procedure G to yield the3-(4-Bromo-phenyl)-(2S)-(5-chloro-2-heptyloxy-benzoylamino)-propionicacid methyl ester (0.500 g).

The title compound was then prepared from3-(4-Bromo-phenyl)-(2S)-(5-chloro-2-heptyloxy-benzoylamino)-propionicacid methyl ester (0.090 g, 0.176 mmol) and 4-trifluoromethoxy boronicacid (0.067 g, 0.352 mmol) with Pd (PPh₃) (0.020 g, 0.0176 mmol) and 2NNa₂CO₃ (0.528 ml, 0.528 mmol) as per general procedure D to yield the(2S)-(5-Chloro-2-heptyloxy-benzoylamino)-3-(4′-trifluoromethoxy-biphenyl-4-yl)-propionicacid methyl ester which was further hydrolyzed as per general procedureC to give the title compound (0.050g). ¹H-NMR(400 MHz, CDCl₃): 1.11 (t,3H), 1.44(m, 8H), 1.87(m, 2H). 3.65(dddd, 2H), 4.27(m, 2H), 5.50(m, 1H),7.18(m, 2H), 7.4(d, 1H), 7.57(m, 4H), 7.68-7.85(m, 4H), 8.52 (S, 1H),8.98 (bs, 1H). LC/MS (m/z): 578.2(M+2).

Example 1242-(S)-(5-Bromo-2-heptyloxy-benzoylamino)-3-[2′-(4-trifluoromethyl-phenoxy)-biphenyl-4-yl]-propionicacid

5-Bromo-2-heptyloxy-benzoic acid was prepared by reacting5-Bromo-2-hydroxy-benzoic acid methyl ester (1.0 g, 4.32 mmol) withIodoheptane (1.46 g, 6.49 mmol) as per general procedure G withpotassium carbonate (1.5 g, 10.8 mmol) added to it. The ester thusobtained was subjected to hydrolysis as per general procedure C to yieldthe 5-Bromo-2-heptyloxy-benzoic acid (0.950 g).

Also the (2S)-Amino-3-(2′-hydroxy-biphenyl-4-yl)-propionic acid wasprepared from (S)-4-bromophenylalanine (5.0 g, 20.48 mmol),2-hydroxyphenylboronic acid (4.23 g, 30.72 mmol) and Pd (PPh₃) 4 (2.36g, 2.038 mmol) as per procedure D to yield the corresponding amino acidwhich was further esterified with methanolic solution containing 2-3 mlof HCl to yield the corresponding HCl salt of the(2S)-Amino-3-(2′-hydroxy-biphenyl-4-yl)-propionic acid methyl ester (5.0g).

5-Bromo-2-heptyloxy-benzoic acid (0.231 g, 0.738 mmol) and the(2S)-Amino-3-(2′-hydroxy-biphenyl-4-yl)-propionic acid methyl ester(0.200 g, 0.738 mmol) were then combined as per general procedure A withHBTU (0.335 g, 0.885 mmol) and diisopropylethylamine (0.285 g, 2.21mmol) to yield the(2S)-(5-Bromo-2-heptyloxy-benzoylamino)-3-(2′-hydroxy-biphenyl-4-yl)-propionicacid methyl ester (0.200 g). The methyl ester of the title compound wasthe prepared from(2S)-(5-Bromo-2-heptyloxy-benzoylamino)-3-(2′-hydroxy-biphenyl-4-yl)-propionicacid methyl ester (0.080 g, 0.140 mmol) and the trifluoromethylboronicacid (0.050 g, 0.281 mmol) as per general procedure F, which was furtherhydrolyzed as per general procedure C to give the title compound (0.020g). ¹H-NMR(400 MHz, CDCl₃): 1.14(t, 3H), 1.53 (m, 8H), 1.92(m, 2H),3.6(m, 2H), 4.21(m, 2H), 5.21(m, 1H), 7.12(d, 1H), 7.22(m, 2H), 7.36(d,1H), 7.5(d, 2H), 7.58(m, 2H), 7.66(m, 1H), 7.78 (m, 6H), 8.62 (S, 1H),8.9 (bs, 1H).

LC/MS (m/z): 700.2(M+2).

By analogous methods to those described above, the following compoundswere synthesized LC/MS EX. NAME (m/z) 1252-(S)-(5-Chloro-2-heptyloxy-benzoylamino)-3-(4′- 537dimethylamino-biphenyl-4-yl)-propionic acid 1262-S)-(5-Chloro-2-heptyloxy-benzoylamino)-3-(3′,4′- 562dichloro-biphenyl-4-yl)-propionic acid 1272-(S)-(5-Bromo-2-heptyloxy-benzoylamino)-3-[2′-(4-tert- 687butyl-phenoxy)-biphenyl-4-yl]-propionic acid 1283-(3′-Chloro-4′-fluoro-biphenyl-4-yl)-2-(S)- 546(5-chloro-2-heptyloxy-benzoylamino)-propionic acid 1292-(S)-(5-Chloro-2-heptyloxy-benzoylamino)-3-(4′- 562trifluoromethyl-biphenyl-4-yl)-propionic acid

Example 1302-(S)-(5-Bromo-2-cyclohexyloxy-benzoylamino)-3-(2′-phenoxy-biphenyl-4-yl)-propionicacid methyl ester

5-Bromo-salicylic acid (2.16 g, 10 mmol) was first transformed into2-acetyl-5-bromo-salicylic acid (252 g) with acetyl chloride (2.34 g, 30mmol) and pyridine (3.95 g, 50 mmol) in DCM, following the generalprocedure K. The above acid (1.29 g, 5.0 mmol) was converted into acidchloride by using oxalyl chloride (1.97 g, 15 mmol) and catalytic amountof DMF in DCM following the general procedure L, then2-(S)-phenoxy-biphenyl alanine (1.45 g, 5.0 mmol) and DIEA (0.77 g, 6.0mmol) were added to the acid chloride to form the coupled product (usingthe general procedure M), which upon hydrolysis with aq. NaHCO₃ gave(2S)-[5-Bromo-2-hydroxybenzoylamine]-3-(2′-phenoxybiphenyl-4-yl)-propionicacid methyl ester (1.92 g). The methyl ester (25 mg, 0.046 mmol) wasthen reacted with iodocyclohexane (19 mg, 0.092 mmol) as described ingeneral procedure G to provide(2S)-(5-Bromo-2-cyclohexyloxy-benzoylamino)-3-(2′-phenoxy-biphenyl-4-yl)-propionicacid methyl ester (26 mg).

¹H NMR (400 MHz, CDCl₃): 1.15-1.45 (m, 7H), 1.75 (m, 1H), 1.95 (m, 1H),3.24 (d, 2H), 3.75 (s, 3H), 4.30 (m, 1H), 5.05 (m, 2H), 6.90 (m, 2H),7.01 (m, 2H), 7.10 (dd, 2H), 7.26 (m, 4H), 7.45 (m, 6H); LC/MS (m/z):629 (M+1)⁺.

Example 1312-S)-(5-Bromo-2-cyclohexyloxy-benzoylamino)-3-(2′-phenoxy-biphenyl-4-yl)-propionicacid

(2S)-[5-Bromo-2-(4-trifluoromethylbenzyloxy)-benzoylamine]-3-(2′-phenoxybiphenyl-4-yl)-propionicacid methyl ester in Example 130 was hydrolyzed following generalprocedure C to give the title compound (22 mg).

¹H NMR (400 MHz, CDCl₃): 1.11-1.25 (m, 7H), 1.70 (m, 1H), 1.90(m, 1H),0.328 (m, 2H), 4.28 (m, 1H), 5.06 (m, 2H), 6.89 (m, 2H), 6.99 (m, 2H),7.17-7.51 (m, 12H); LC/MS (m/z): 615 (M+1)⁺.

By analogous methods to those described above the following compoundswere synthesized. LC/MS EX. NAME (m/z) 1323-Biphenyl-4-yl-2-(5-bromo-2-heptyloxy-benzoylamino)- 539 propionic acid133 3-Biphenyl-4-yl-2-(S)-[2-(4-tert-butyl-benzyloxy)-5- 542chlorobenzoyl amino]-propionic acid 1342-(S)-[5-Bromo-2-(4-[1,2,4]triazol-1-yl-benzyloxy)- 690benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid 1352-(S)-[5-Bromo-2-(4-tert-butyl-benzyloxy)- 679benzoylamino]-3-(2′-phenoxy-biphenyl-4- yl)-propionic acid

Example 1362-S)-(2-Benzyloxy-5-bromo-benzoylamino)-3-biphenyl-4-yl-propionic acid

3-Biphenyl-4-yl-2-(S)-(5-bromo-2-hydroxy-benzoylamino)-propionic acidmethyl ester (425 mg) was prepared from2-(S)-amino-3-biphenyl-4-yl-propionic acid methyl ester-hydrochloride(1.0 g, 3.4 mmol), and 5-bromo-2-hydroxy-benzoic acid (744 mg, 3.4 mmol)as described in general procedure A except for an adapted work-up. Afterreaction completion, the reaction mixture was poured onto 150 mL of 1NHCl and 150 mL of EtOAc. The organic layer was washed with 1N HCl,saturated sodium bicarbonate, dried over sodium sulfate and evaporated.The crude material was purified over silica gel (8:2, DCM-hexanes).

2-(S)-(2-Benzyloxy-5-bromo-benzoylamino)-3-biphenyl-4-yl-propionic acidmethyl ester (82 mg) was prepared from3-biphenyl-4-yl-2-(S)-(5-bromo-2-hydroxy-benzoylamino)-propionic acidmethyl ester (150 mg, 0.33 mmol) and benzyl bromide (0.047 mL, 0.40mmol) as described in general procedure G and purified over silica gel(7:3, DCM-hexanes).

2-(S)-(2-Benzyloxy-5-bromo-benzoylamino)-3-biphenyl-4-yl-propionic acidmethyl ester (50 mg, 0.092 mmol) was dissolved in 5 mL of THF-MeOH(4-1), cooled to 0° C. and 1.1 equiv of 2 N LiOH added. After 30minutes, 3.3 additional equiv of 2N LiOH was added and the reactionstirred for 60 minutes. The reaction was worked up according to generalprocedure C to give2-(S)-(2-benzyloxy-5-bromo-benzoylamino)-3-biphenyl-4-yl-propionic acid(34 mg)

¹H-NMR(400 MHz, DMSO-d₆): 2.92 (m, 1H), 3.17 (m, 1H), 4.71 (m, 1H), 5.25(m, 2H), 7.18 (m, 3H), 7.28-7.42 (m, 8H), 7.52-7.64 (m, 5H), 7.81 (m,1H), 7.52 (d, 1H); LC/MS (m/z): 532.0 (M+1)⁺.

Example 1373-Biphenyl-4-yl-2-(S)-[2-(3,4-bis-benzyloxy-benzyloxy)-5-bromo-benzoylamino]-propionicacid

3-Biphenyl-4-yl-2-S)-[2-(3,4-bis-benzyloxy-benzyloxy)-5-bromo-benzoylamino]-propionicacid methyl ester (340 mg) was prepared from3-biphenyl-4-yl-2-(S)-(5-bromo-2-hydroxy-benzoylamino)-propionic acidmethyl ester (400 mg, 0.92 mmol) (See example 136) and1,2-bis-benzyloxy-4-chloromethyl-benzene (374 mg, 1.1 mmol) as describedin general procedure G and purified over silica gel (8:2, DCM-hexanes).

3-Biphenyl-4-yl-2-(S)-[2-(3,4-bis-benzyloxy-benzyloxy)-5-bromo-benzoylamino]-propionicacid methyl ester (60 mg, 0.079 mmol) was dissolved in 5 mL of THF-MeOH(4-1), cooled to 0° C. and 1.1 equiv of 2 N LiOH added. After 30minutes, 2.2 additional equiv of 2N LiOH was added and the reactionstirred for 30 minutes. The reaction was worked up according to generalprocedure C to give3-biphenyl-4-yl-2-(S)-[2-(3,4-bis-benzyloxy-benzyloxy)-5-bromo-benzoylamino]-propionicacid (47 mg). ¹H-NMR(400 MHz, DMSO-d₆): 2.83 (m, 1H), 3.13 (m, 1H), 4.67(m, 1H), 5.02 (s, 2H), 5.06 (s, 2H), 5.17, (m, 2H), 6.92 (m, 1H), 6.96(m, 1H), 7.13 (d, 2H), 7.18-7.22 (m, 2H), 7.27-7.41 (m, 13H), 7.44 (d,2H), 7.56 (m, 2H), 7.61 (m, 1H), 7.83 (m, 1H), 8.50 (d, 1H); LC/MS(m/z): 742 (M+1)⁺.

Example 1383-Biphenyl-4-yl-2-(S)-([4-(4-tert-butyl-benzyloxy)-4′-trifluoromethyl-biphenyl-3-carbonyl]-amino}-propionicacid

The chloro compound (Example 133,100 mg, 0.15 mmol) was reacted with4-trifluoromethyl-phenyboronic acid (87.5 mg, 4.5 mmol) as described ingeneral procedure D yielding the title compound (85 mg) as white solid.LC/MS (m/z): 651 (M+1)⁺.

Example 1393-Biphenyl-4-yl-2-(S)-{[4-(4-tert-butyl-benzoylamino)-3′-trifluoromethylbiphenyl-3-carbonyl]-amino}-propionic acid

(2S)-(2-Amino-5-iodo-benzoyl-amino)-3-biphenyl-4-yl-propionic acidmethyl ester (1.53 g) was prepared from(2S)-amino-3-biphenyl-4-yl-propionic acid methyl ester (1.0 g, 4.1mmol), 5-iodo-2-amino-benzoic acid (1.23 g, 4.9 mmol) as described ingeneral procedure A.

To a stirring solution of(2S)-(2-amino-5-iodo-benzoyl-amino)-3-biphenyl-4-yl-propionic acidmethyl ester (1.0 g, 2 mmol) prepared above dissolved in DCM containingpyridine (1.58 g, 4 mmol ), was added t-butyl-benzoyl chloride (1.20 g,2.5 mmol) at 0° C. The reaction mixture was stirred at rt for 3 h,extracted with DCM, washed with 1M HCl and brine evaporation followed bycolumn chromatography purification (silica, CH₂Cl₂) giving3-biphenyl-4-yl-(2S)-[2-(4-tert-butyl-benzoylamino)-5-iodo-benzoyl-amino]-propionicacid methyl ester (1.25 g) as a white solid which was hydrolyzedaccording to general procedure C yielding the title compound (1.23 g,100%) as a white solid. ¹H-NMR(400 MHz, DMSO-d₆): 1.26 (s, 9H),3.09-3.19 (m, 1H), 3.21-3.29 (m, 1H), 4.74-4.76 (m, 1H), 7.27-7.29 (m,1H ), 7.42-7.39 (m, 4H), 7.44-7.57 (m, 7H), 7.67-7.77 (m, 3H), 7.99 (s,1H), 8.54 (d, 1H, J=8.0 Hz), 9.32 (d, 1H, J=8.0 Hz), 11.98 (s, 1H);

LC/MS (m/z): 647 (M+1)⁺.

The iodo derivative (100 mg, 0.15 mmol) was reacted with3-trifluoromethyl phenyl boronic acid (87.5 mg, 4.5 mmol) as describedin general procedure D yielding the title compound (92 mg) as whitesolid. LC/MS (m/z): 665 (M+1)⁺.

Example 1403-Biphenyl-4-yl-2-(S)-[(5-chloro-2,4-dimethoxy-4′-trifluoromethyl-biphenyl-3-carbonyl)-amino]-propionicacid

2-(S)-amino-3-biphenyl-4-yl-propionic acid methyl ester (128 mg, 0.5mmol) was reacted with 3-bromo-5-chloro-2,6-dimethoxybenzoic acid (148mg, 0.5 mmol) as described in general procedure A. The resulting crudecompound was reacted with 195 mg (1.0 mmol) of4-(trifluoromethyl)phenylboronic acid as described in general procedureD. The product thus obtained was hydrolyzed according to generalprocedure C to afford the title product (180 mg) as a pure white solid.

LC/MS (m/z): 584 (M+1)⁺.

Example 1413-Biphenyl-4-yl-2-(S)-(3-bromo-5-chloro-2,6-dimethoxy-benzoylamino)-propionicacid

2-(S)-amino-3-biphenyl-4-yl-propionic acid methyl ester (128 mg, 0.5mmol) was reacted with 3-bromo-5-chloro-2,6-dimethoxybenzoic acid (148mg, 0.5 mmol) as described in general procedure A. The resultingcompound was hydrolyzed according to general procedure C to afford thetitle product (209 mg) as a pure white solid.

LC/MS (m/z): 519 (M+1)⁺.

Example 1423-(3′-Chloro-4′-fluoro-biphenyl-4-yl)-2-(S)-[(4-methoxy-4′-trifluoromethyl-biphenyl-3-carbonyl)-amino]-propionicacid methyl ester

3-(3′-Chloro-4′-fluoro-biphenyl-4-yl)-2-(S)-[(4-methoxy-4′-trifluoromethyl-biphenyl-3-carbonyl)-amino]-propionicacid methyl ester (223 mg, ) was prepared from4-Methoxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid (141 mg, 0.5mmol) and S-2-amino-3-(3′-chloro-4′-fluoro-biphenyl-4-yl)-propionic acidmethyl ester (155 mg, 0.5 mmol) following the general procedure A.

LC-MS (m/z): 586 (M+1)⁺; ¹H NMR (400 MHz, CDCl₃): 63.24-3.38 (m, 2H),3.76 (m, 1H), 3.80 (s, 3H), 3.90 (s, 3H), 5.14 (q, 1H), 6.68 (d, 1H),7.06 (q, 1H), 7.18 (q, 1H), 7.24 (m, 3H), 7.44 (m, 2H), 7.52-7.60 (m,2H), 7.68-7.72 (m, 3H) and 8.16 (dd, 1H).

Example 1432-(S)-[(4-Acetoxy-4′-trifluoromethyl-biphenyl-3-carbonyl)-amino]-3-(3′-chloro-4′-fluoro-biphenyl-4-yl)-propionicacid methyl ester

Acetic acid 3-chlorocarbonyl-4′-trifluoromethyl-biphenyl-4-yl ester (334mg) was prepared from 4-acetoxy-4′-trifluoromethyl-biphenyl-3-carboxylicacid (324 mg, 1.0 mmol) following the general procedure L.

2-(S)-[(4-Acetoxy-4′-trifluoromethyl-biphenyl-3-carbonyl)-amino]-3-(3′-chloro-4′-fluoro-biphenyl-4-yl)-propionicacid methyl ester (278 mg) was prepared from acetic acid3-chlorocarbonyl-4′-trifluoromethyl-biphenyl-4-yl ester (171 mg, 0.5mmol) and 2-(S)-amino-3-(3′-chloro-4′-fluoro-biphenyl-4-yl)-propionicacid methyl ester (155 mg, 0.5 mmol) following the general procedure M.

LC-MS (m/z): 614 (M+1)⁺; ¹H NMR (400 MHz, CDCl₃): δ 2.05 (s, 3H), 3.24(dd, 1H), 3.46 (dd, 1H), 3.70 (m, 1H), 3.84 (s, 3H), 5.13 (q, 1H), 7.16(d, 2H), 7.18 (d, 1H), 7.22 (d, 1H), 7.38 (m, 1H), 7.43 (d, 2H), 7.49(d, 1H), 7.60 (dd, 1H), 7.70 (s, 2H), 7.72 (d, 1H), 7.74 (d, 1H), and8.26 (d, 1H).

Example 144N-[4-(2,4-Dichloro-6-methyl-phenoxy)-2-hydroxy-phenyl]-2-(3′-trifluoromethyl-biphenyl-4-yl)-acetamide

The resin-bound2-(4-bromo-phenyl)-N-[2-Hydroxy-4-(3,4-dichloro-6-methyl-phenoxy)-phenyl]-acetamide(120 mg, 0.1 mmol, obtained from coupling reaction between the resinbound 2-Amino-5-(2,4-dichloro-6-methyl-phenoxy)-phenol and 4-bromophenylacetic acid following the general procedure A) was reacted with3-trifluormethyl-phenyl boronic acid (56.7 mg, 0.3 mmol) as described inthe general procedure D followed by cleavage as described in example 1,to afford (27.5 mg) of title compound.

¹H NMR (400 MHz, CDCl₃): 2.13 (s, 1H), 3.86 (s, 2H), 6.33 (dd, 1H,J=8.8, 2.4 Hz), 6.37 (d, 1H, J=2.4 Hz), 6.69 (d, 1H, J=8.8 Hz), 7.15 (m,1H), 7.30 (d, 1H, J=0.8 Hz), 7.45 (dd, 2H, J=6.4, 2.0 Hz), 7.59-7.65 (m,4H), 7.78 (m, 1H), 7.84 (s, 1H), 8.84 (s, 1 H); LC/MS (m/z): 546 (M+1)⁺.

Example 145 2-(4-tert-Butyl-benzoylamino)-benzoic acid methyl-amide

The 2-aminobenzoic acid (137 mg, 1.0 mmol) was reacted with 4-tert-butylbenzoyl chloride (196 mg, 1.0 mmol) as described in general procedure M.The resulting compound was coupled with methylamine (62 mg, 2.0 mmol) asdescribed in general procedure A to afford the title product (186 mg) asa pure white solid.

LC/MS (m/z): 311 (M+1)⁺.

Example 1462-(S)-[(3-Hydroxy-naphthalene-2-carbonyl)-(4-pyridin-3-yl-benzyl)-amino]-3-(4-pyridin-3-yl-phenyl)-propionicacid

1.0 g (2.5 mmol) of resin-bound naphthoic acid obtained in Example 1 wasreacted with 1.95 g (7.5 mmol) of (2S)-Amino-3-(4-bromophenyl)-propionicacid methyl ester as described in the general procedure A to giveresin-bound2-(S)-(3-Hydroxy-naphthalene-2-carbonyl)-amino-3-(4-bromophenyl)-propionicacid methyl ester.

0.05 g (0.1 mmol) of the above resin was treated with 4-bromobenzylbromide (75 mg, 0.30 mmol), and Lithium tert-butoxide (0.6 mmol) in THFat RT for 6h, followed by 3-pyridyl boronic acid (123 mg, 1.0 mmol) asdemonstrated in the general procedure D followed by the cleavage of theresin to afford 18 mg of the title compound. LC/MS (m/z) 594 (M+1)⁺.

Example 1473-Biphenyl-4-yl-2-(S)-{[5-(3-trifluoromethoxy-phenoxymethyl)-pyrazine-2-carbonyl]-amino}-propionicacid

To a solution of 5-methyl-pyrazine-2-carboxylic acid methyl ester (2.0g, 13.146 mmol) in CCl4 (25 mL0 was added NBS (2.57 g, 14.461 mmol) andbenzoyl peroxide (0.318 g, 1.314 mmol) and the solution was heated at 70C. for 1 h. Upon cooling to RT, the organic layer was washed withNaHCO₃, water, dried (Na₂SO₄), and concentrated under reduced pressureto give 0.900 g 5-Bromomethyl-pyrazine-2-carboxylic acid methyl ester.

A solution of 5-bromomethyl-pyrazine-2-carboxylic acid methyl ester(0.305 g, 1.314 mmol) in DMF (6 mL) was treated with3-trifluoromethoxyphenol (0.280 g, 1.577 mmol) and potassium carbonate(0.400 g, 2.89 mmol) by the general procedure G. The crude product waspurified by flash column chromatography on silica gel to give 0.380 g ofpure 5-(3-Trifluoromethoxy-phenoxymethyl)-pyrazine-2-carboxylic acidmethyl ester. LCMS: 330 (M+2)⁺

A solution of 5-(3-trifluoromethoxy-phenoxymethyl)-pyrazine-2-carboxylicacid methyl ester (0.234 g, 0.712 mmol) in THF:MeOH (4:1, 5 mL) wastreated with LiOH (0.150 g, 3.564 mmol) in 1.5 mL of water by thegeneral procedure C to give 0.182 g of5-(3-trifluoromethoxy-phenoxymethyl)-pyrazine-2-carboxylic acid. LCMS:316 (M+2)⁺

A solution of 5-(3-trifluoromethoxy-phenoxymethyl)-pyrazine-2-carboxylicacid (0.182 g, 0.579 mmol) was treated with2(S)-amino-3-biphenyl-4-yl-propionic acid methyl ester hydrochloride(0.162 g, 0.637 mmol), HBTU (0.440 g, 1.158 mmol), and DIEA (0.310 g,1.737 mmol) by the general procedure A. The crude crude product waspurified by flash column chromatography on silica gel to give 0.170 g of3-biphenyl-4-yl-2(S)-{[5-(3-trifluoromethoxy-phenoxymethyl)-pyrazine-2-carbonyl]-amino}-propionicacid methyl ester. LCMS: 553 (M+2)⁺

A solution ofbiphenyl-4-yl-2(S)-{[5-(3-trifluoromethoxy-phenoxymethyl)-pyrazine-2-carbonyl]-amino}-propionicacid methyl ester (0.170 g, 0.308 mmol) in THF:MeOH (4:1, 5 mL) wastreated with LiOH (0.064 g, 1.54 mmol) in 1.5 mL of water by the generalprocedure C to give 0.140 g of pure3-biphenyl-4-yl-2(S)-{[5-(3-trifluoromethoxy-phenoxymethyl)-pyrazine-2-carbonyl]-amino}-propionicacid as a white solid. LCMS: 539 (M+2)⁺

Example 148 4-Hydroxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid[2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-methoxymethyl-ethyl]-amide

2-(R)-tert-Butoxycarbonylamino-3-(3′-chloro-4′-fluoro-biphenyl-4-yl)-propionicacid (2.0 g, 5.07 mmol) was dissolved in 15 mL anhydrous THF and BH₃:THF(11 mL, 11.0 mmol, 1M solution in THF) was added drop wise at 0° C. andstirred for 10 h at room temperature. Excess BH₃:THF was quenched byadding methanol (˜1 mL) at 0° C. Solvent was removed under vacuum andresidue was dissolved in EtOAc (20 mL) and washed with water, brine anddried over Na₂SO₄. Solvent was removed under vacuum and silica gelcolumn chromatography (CH₂Cl₂:MeOH) gave pure[1-(3′-Chloro-4′-fluoro-biphenyl-4-ylmethyl)-2-(R)-hydroxy-ethyl]-carbamicacid tert-butyl ester as white solid (1.6 g)

NaH (55 mg, 1.31 mmol, 60% by wt suspension in mineral oil) was added at0° C. to a solution of[1-(3′-Chloro-4′-fluoro-biphenyl-4-ylmethyl)-2-(R)-hydroxy-ethyl]-carbamicacid tert-butyl ester (0.5 g, 1.31 mmol) in 5 mL anhydrous THF andstirred for 20 min at 0° C. Mel (0.37 g, 2.63 mmol) was added to thereaction mixture and stirred for 6 h at room temperature. Reactionmixture was diluted with 5 mL EtOAc, and washed with water, brine anddried over Na₂SO₄. Solvent was removed under vacuum and silica gelchromatography (EtOAc:Hexanes) gave pure[1-(3′-Chloro4′-fluoro-biphenyl-4-ylmethyl)-2-(R)-methoxy-ethyl]-carbamicacid tert-butyl ester (0.38 g).

[1-(3′-Chloro-4′-fluoro-biphenyl-4-ylmethyl)-2-(R)-methoxy-ethyl]-carbamicacid tert-butyl ester was converted to corresponding1-(3′-Chloro-4′-fluoro-biphenyl-4-ylmethyl)-2-methoxy-ethylaminehydrochloride salt according to the general procedure N.

4-Methoxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid[2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-methoxymethyl-ethyl]-amide(45 mg) was prepared from1-(3′-Chloro-4′-fluoro-biphenyl-4-ylmethyl)-2-methoxy-ethylaminehydrochloride salt (35 mg, 0.1 mmol) and4-Methoxy-4′-trifluoromethyl-biphenyl-3-carbonyl chloride (32 mg, 0.1mmol) in presence of triethyl amine (41 mg, 0.41 mmol) according to thegeneral procedure M.

¹HNMR (400 MHz, CDCl₃): 3.00 (dd, 1H), 3.10 (dd, 1H), 3.37-3.50 (m, 5H),3.99 (s, 3H), 4.50-4.61 (m, 1H), 7.07(d, 1H), 7.19 (t, 1H), 7.34-7.51(m, 5H), 7.60 (dd, 1H), 7.74-7.76 (m, 5H), 8.25 (d, 1H), 8.50 (d, 1H),

LC/MS (m/z): 572.2 (M+1)⁺.

BBr₃:DMS (13 mg, 0.04 mmol) was added to a solution of4-Methoxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid[2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-methoxymethyl-ethyl]-amide(24 mg, 0.04 mmol) in 3 mL of anhydrous CH₂Cl₂, at −78° C. and slowlyallowed to come to room temperature and stirred for 2 h. Aftercompletion of the reaction, reaction was cooled to −78° C. and 0.5 mL ofMeOH was added, solvent was removed under vacuum and the residue wastaken in ethyl acetate (4 mL) and washed with aq NaHCO₃ solution, water,brine and dried over Na₂SO₄. Solvent was removed under vacuum and silicagel column chromatography (Ethyl acetate: Hexanes) gave pure4-Hydroxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid[2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-methoxymethyl-ethyl]-amide(14 mg).

¹HNMR (400 MHz, CDCl₃): 3.00 (dd, 1H), 3.10 (dd, 1H), 3.38-3.60 (m, 5H),4.44-4.60 (m, 1H), 6.75 (d, 1H), 7.09 (d, 1H), 7.16-7.23 (m, 1H),7.30-7.75 (m, 12H), 12.4 (s, 1H).

LC/MS (m/z): 558.1 (M+1)⁺.

Example 1493-[4-(4-Cyano-phenoxy)-phenyl]-(2S)-[(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionicacid methyl ester

3-(4-Hydroxy-phenyl)-(2S)-[4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionicacid methyl ester (664 mg) was prepared starting from4′-trifluoromethyl-biphenyl-4-carboxylic acid (532 mg, 2.0 mmol) andtyrosine methyl ester (462 mg, 2.0 mmol) according to general procedureA. The above compound (443 mg, 1.0 mmol) was treated with1-fluoro-4-cyanobenzene (181 mg, 1.5 mmol) following general procedure Bto give3-[4-(4-cyano-phenoxy)-phenyl]-(2S)-[(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionicacid methyl ester (360 mg). The ester was hydrolyzed following generalprocedure C to give the title compound (345 mg)

¹H NMR (400 MHz, CDCl₃): 3.28, 3.44 (ABX, 2H), 5.12 (dd, 1H), 6.65 (d,1H), 6.99 (m, 4H), 7.28 (m, 2H), 7.58 (d, 2H), 7.69 (m, 6H), 7.84 (d,2H); LC/MS (m/z): 530 (M+1)⁺; LC/MS:545.

Example 1503-(4′-Trifluoromethyl-biphenyl-4-yl)-2-[4-(5-trifluoromethyl-pyridin-2-yloxy)-benzoylamino]-propionicacid methyl ester

4-(5-Trifluoromethyl-pyridin-2-yloxy)-benzaldehyde was prepared from4-fluorobenzaldehyde (2.48 g, 20 mmol) and2-hydroxy-5-trifluoromethylpyridine (3.29 g, 20 mmol) following generalprocedure B. (4.62 g)

To aq. NaOH (3.2 g, 80 mmol) was added silver nitrate (3.4 g, 40 mmol)and stirred for 10 min., then the mixture was cooled to 0° C. and theabove aldehyde (4.62 g, 17 mmol) was added. The mixture was stirredovernight, then filtrate through celite. The filtrate was collected andacidified with conc. HCl. The solid was collected by filtration anddried under vacuum to give 4-(5-trifluoromethyl-pyridin-2-yloxy)-benzoicacid. (3.5 g)

The title compound was prepared from4-(5-trifluoromethyl-pyridin-2-yloxy)-benzoic acid (283 mg, 1.0 mmol)and 2-amino-3-(4′-trifluoromethyl-biphenyl-4-yl)-propionic acid methylester (360 mg, 1.0 mmol) following general procedure A. (580 mg)¹H-NMR(400 MHz, CD₃COCD₃): 3.24 (dd, 1H), 3.39 (dd, 1H), 3.74 (s, 3H),4.98 (m, 1H), 6.64 (d, 1H), 7.50 (m, 2H), 7.60 (m, 2H), 7.69 (m, 3H),7.78 (d, 2H), 7.88 (d, 2H), 7.98(m, 2H), 8.15 (m, 2H); LC/MS (m/z): 589(M+1)⁺.

By analogous methods to those described above, the following compoundwas synthesized LC/MS EX. NAME (m/z) 1513-(4′-Trifluoromethoxy-biphenyl-4-yl)-2-(S)-[4-(5- 604.5trifluoromethyl-pyridin-2-yloxy)-benzoylamino]- propionic acid methylesterBiological Assay

The following assay methods may be used to identify compounds of Formula(I) that are effective in showing antiviral activity against vacciniavirus.

General Assay Procedures

Cytopathic effect was measured on the BSC40 african green monkey kidneycells using 100 μM concentrations of the compounds of Formula (I). Inthis assay, 96-well black Packard viewplates were seeded with BSC40cells (2.25×10⁴ cells/well) in Minimum Essential Media supplemented with5% FCS, 2 mM L-glutamine and 10 μg/mL gentamycin sulfate. When the cellsbecame confluent (24 hrs) they were treated with 100 μM compound dilutedin media. The cells were place in an incubator at 37° C. (5% CO₂) for 24hours, and checked for toxicity via direct observation under themicroscope and also with alamar blue which assesses cell viability andproliferation (healthy cells produce a visible color change from blue tored). The cells were scored on a scale of 0-3 where 0 corresponds tonormal healthy cells, 1 corresponds to sick cells but not rounding up, 2corresponds to cells that are rounding up, and 3 corresponds to cellsthat have rounded up and pulled off the plate. Compounds atconcentrations that scored 1 or greater were diluted and the above assaywas repeated to find the concentration at which the compound scored 0.

A vaccinia virus green fluorescent protein (vvGFP) assay was performedto test the ability of compounds of Formula (I) to inhibit viral growthas measured by a reduction in fluorescence from vaccinia virusexpressing the green fluorescent protein. In this assay, 96-well blackPackard viewplates were seeded with BSC40 cells in Minimum EssentialMedia supplemented with 5% FCS, 2 mM L-glutamine and 10 μg/mL gentamycinsulfate. When the cells became confluent, they were washed with PBS andthen infected with vaccinia virus at a multiplicity of infection (moi)of 0.1 for 30 min in PBS. At 30 minutes, the cells were overlaid with100 μl of infection media supplemented with 100 μM test compound. Ascontrols infected cells are treated with rifampicin (blocks assembly ofDNA and protein into mature virus particles), with no compound, or mockinfected. Cells were placed in an incubator at 37° C. (5% CO₂) for 24hrs. At 24 hours post infection (hpi), the plates were removed from theincubator, washed with PBS and fluorescence measure on a Wallac platereader (excite at 485 nm and read at 535 nm). Wells that showed reducedfluorescence were checked visually under the microscope to verify areduction in viral infection versus a loss of cells due to cytopathiceffect from virus infection. Compounds that are found to inhibit viralreplication were then checked for inhibitory effect at variousconcentrations to determine the IC₅₀ and the therapeutic index.

The compounds of Formula (I) listed in Table 1 have an IC₅₀ of less thanor equal to about 100 μM.

While the invention has been described and illustrated with reference tocertain embodiments thereof, those skilled in the art will appreciatethat various changes, modifications and substitutions can be madetherein without departing from the spirit and scope of the invention.For example, effective dosages other than the dosages as set forthherein may be applicable as a consequence of variations in theresponsiveness of the mammal being treated for orthopox -mediateddisease(s). Likewise, the specific pharmacological responses observedmay vary according to and depending on the particular active compoundselected or whether there are present pharmaceutical carriers, as wellas the type of formulation and mode of administration employed, and suchexpected variations or differences in the results are contemplated inaccordance with the objects and practices of the present invention.

1. The compound of Formula (I):

wherein c is equal to 0, 1, or 2; wherein the values of 0, 1, and 2comprise a direct bond, —CH₂—, and —CH₂—CH₂—, optionally substituted 1to 4 times with a substituent group, wherein said substituent group(s)or the term substituted refers to groups comprising: -alkyl, -aryl,-alkylene-aryl, -arylene-alkyl, -alkylene-arylene-alkyl, —O-alkyl,—O-aryl, or -hydroxyl; G comprises: -hydrogen, -alkyl, -heteroaryl,-aryl, -heterocyclycl, —CH═CH—CO₂R₁, —CO₂R₁, —CH₂OR₁, —CH₂SR, —C(O)—R₁,—C(O)NR₁R₂, —C(R₁)═N—O—R₂, —C(O)C(O)R₁, —C(O)C(O)NR₁R₂, —CH═CH—NO₂,—CH═CH—CN, —C(O)—C(O)—OR₁, an acid isostere, or an ester isostere;wherein R₁ and R₂ independently comprise: -hydrogen, -alkyl, -aryl,-alkenyl, -arylene-alkyl, -alkylene-aryl, -alkylene-arylene-alkyl,-heterocyclyl, or -heteroaryl; or when R₁ and R₂ are bonded to anitrogen group in G, R₁ and R₂ may be taken together to form a ringhaving the formula —(CH₂)_(m)-Z₂(CH₂)_(n)—, wherein m and n are,independently, 1, 2, 3, or 4 and Z₂ comprises —CH₂—, —C(O)—, —O—,—N(H)—, —S—, —S(O)—, —S(O₂)—, —CON(H)—, —NHC(O)—, —NHC(O)N(H)—,—NH(SO₂)—, —S(O₂)N(H)—, —(O)CO—, —NHS(O₂)NH—, —OC(O)—, —N(R₂₁)—,—N(C(O)R₂₁)—, —N(C(O)NHR₂₁)—, —N(S(O₂)NHR₂₁)—, —N(SO₂R₂₁)—, or—N(C(O)OR₂₁)—; wherein R₂₁ comprises hydrogen, aryl, alkyl, oralkylene-aryl; or R₂ comprises a substituent of the formula

wherein L₁ comprises a direct bond, alkylene, —O-alkylene-, alkylene-O—,—NH—C(O)—, —C(O)—NH— or —NH—C(O)—NH—; L₂ comprises alkyline, alkenyline,heteroaryline, aryline, or heterocyclyline; L₃ comprises —O—, —N(R₃)—,—C(O)—N(R₃)—, —C(O)—O—, —C(O)—, —N(R₃)—C(O)—N(R₄)—, —CH═CH—CO₂R₁,—C(O)R₁, —C(O)C(O)R₁, or —C(O)C(O)NR₁R₂; L₄ comprises hydrogen, alkyl,alkenyl, alkynyl, heterocyclyl, heteroaryl, or -alkylene-aryl; and L₅comprises hydrogen, alkyl, alkenyl, alkynyl, -akylene-aryl,-alkylene-heteroaryl, alkylene-O-alkylene-aryl,-alkylene-S-alkylene-aryl, -alkylene-O-alkyl, -alkylene-S-alkyl,-alkylene-NH₂, -alkylene-OH, -alkylene-SH, -alkylene-C(O)-OR₅,-alkylene-C(O)—NR₅R₆, -alkylene-NR₅R₆, -alkylene-N(R₅)—C(O)—R₆, or-alkylene-N(R₅)—S(O₂)—R₆; or

may be taken together to constitute a direct bond; wherein R₃, R₄, R₅,and R₆ independently comprise hydrogen, aryl, heteroaryl, alkyl,-alkylene-aryl, or, -alkylene-heteroaryl; V comprises:—(CH₂)_(b)—O—(CH₂)_(a)—, —(CH₂)_(b)—N(R₈)—(CH₂)_(a)—, —(CH₂)_(b)—O—,—(CH₂)_(b)—N(R₈), —(CH₂)_(a)—, —CH═CH—(R₈)— or a direct bond; in which ais equal to 0, 1, or 2, b is equal to 1 or 2, and R₈ comprises:-hydrogen, -alkyl, -aryl, -arylene-alkyl, -alkylene-aryl, or-alkylene-arylene-alkyl; wherein the —CH₂— groups may be optionallysubstituted 1 to 4 times with a substituent group comprising: -alkyl,-aryl, -alkylene-aryl, -arylene-alkyl, -alkylene-arylene-alkyl,—O-alkyl, —O-aryl, -hydroxyl, —S-alkyl, or —S-aryl; X comprises:—N(R₉)—, —CON(R₉)—, —N(R₉)CO—, —N(R₉)CON(R₁₀)—, —OC(O)N(R₈)—,—SO₂N(R₉)—, —N(R₉)SO₂—, or —N(R₉)SO₂N(R₂₀)—; wherein R₉ and R₁₀independently comprise: -hydrogen, -alkyl, -aryl, -arylene-alkyl,-alkylene-aryl, -alkylene-arylene-alkyl, or —(CH₂)_(d)Y—, wherein d isequal to 0, 1, or 2, wherein Y comprises: -hydrogen, —CO₂R₁₁, —CH₂OR₁₁,—C(O)—R₁₁, —C(O)NR₁₁R₁₂, —C(R₁₁)═N—O—R₁₂, —NR₁₁R₁₂, or an acid isostere;wherein R₁₁ and R₁₂ independently comprise: -hydrogen, -alkyl, -aryl,-arylene-alkyl, -alkylene-aryl, -alkylene-arylene-alkyl, -heterocyclyl,or -heteroaryl; Ar, comprises an aryl, heteroaryl, fused cycloalkylaryl,fused cycloalkylheteroaryl, fused heterocyclylaryl, or fusedheterocyclylheteroaryl group optionally substituted 1 to 7 times,wherein the substitutents independently comprise: a) -fluoro; b)-chloro; c) -bromo; d) -iodo; e) -cyano; f) -nitro; g) -perfluoroalkyl;h) -D-R₁₂; i) -alkyl; j) -aryl; k) -heteroaryl; l) -heterocyclyl; m)-cycloalkyl; n) -alkylene-aryl; o) -alkylene-arylene-aryl; p)-alkylene-arylene-alkyl; q) -arylene-alkyl; r) -arylene-arylene-alkyl;s) -D-alkyl; t) -D-aryl; u) -D-alkylene-aryl; v) -D-arylene-alkyl; w)-D-alkylene-arylene-aryl; x) -D-arylene-arylene-aryl; y)-D-alkylene-arylene-alkyl; z) -alkylene-D-alkylene-aryl; aa)-arylene-D-alkyl; bb)-alkylene-D-aryl; cc) -alkylene-D-heteroaryl; dd)-alkylene-D-cycloalkyl; ee) -alkylene-D-heterocyclyl; ff)-alkylene-D-arylene-alkyl; gg) -alkylene-D-alkylene-arylene-alkyl; hh)-alkylene-D-alkyl; ii) -alkylene-D-R₁₃; jj) -arylene-D-R₁₃; or kk)-hydrogen; wherein D comprises —CH₂—, —O—, —N(R₁₄)—, —C(O)—, —CON(R₁₄)—,—N(R₁₄)C(O)—, —N(R₁₄)CON(R₁₅)—, —N(R₁₄)C(O)O—, —OC(O)N(R₁₄)—,—N(R₁₄)SO₂—, —SO₂N(R₁₄)—, —C(O)—O—, —O—C(O)—, —S—, —S(O)—, —S(O₂)—,—N(R₁₄)SO₂N(R₁₅)—,

wherein R₁₃, R₁₄, R₁₅, and R₁₆ independently comprise: -hydrogen,hydroxyl, -cyano, nitro, -alkyl, -aryl, -arylene-alkyl, -alkylene-aryl,or -alkylene-arylene-alkyl; and Ar₂ comprises an aryl or heteroarylgroup optionally substituted 1 to 7 times, wherein the substitutentsindependently comprise: a) -fluoro; b) -chloro; c) -bromo; d) -iodo; e)-cyano; f) -nitro; g) -perfluoroalkyl; h) -T-R₁₇; i) -alkyl; j) -aryl;k) -heteroaryl; l) -heterocyclyl; m) -cycloalkyl; n) -alkylene-aryl; o)-alkylene-arylene-aryl; p) -alkylene-arylene-alkyl; q) -arylene-alkyl;r) -arylene-arylene-alkyl; s) -T-alkyl; t) -T-aryl; u) -T-alkylene-aryl;v) -T-arylene-alkyl; w) -T-alkylene-arylene-aryl; x)-T-arylene-arylene-aryl; y) -T-alkylene-arylene-alkyl; z)-alkylene-T-alkylene-aryl; aa) -arylene-T-alkyl; bb) -alkylene-T-aryl;cc) -alkylene-T-heteroaryl; dd) -alkylene-T-cycloalkyl; ee)-alkylene-T-heterocyclyl; ff) -alkylene-T-arylene-alkyl; gg)-alkylene-T-alkylene-arylene-alkyl; hh) -alkylene-T-alkyl; ii)-alkylene-T-R₁₇; jj) -arylene-T-R₁₇; or kk)-T-alkylene-arylene-heteroaryl; ll) -T-alkylene-heterocyclyl; mm)-T-alkylene-heteroaryl; nn) -T-heteroaryl; oo) -T-fusedheterocyclylaryl; pp) -T-fused cycloalkylaryl; qq) -T-fusedarylcycloalkyl; rr) -T-fused fused heterocyclylaryl; ss) -T-fused fusedarylheterocyclyl; tt) -T-fused fused cycloalkylheteroaryl; uu) -T-fusedfused heteroarylcycloalkyl; vv) -T-fused heterocyclylheteroaryl;ww)-T-fused heteroarylheterocyclyl; or xx) -hydrogen; wherein Tcomprises a direct bond, —CH₂—, —O—, —N(R₁₈)—, —C(O)—, —CON(R₁₈)—,—N(R₁₈)C(O)—, —N(R₁₈)CON(R₁₉)—, —N(R₁₈)C(O)O—, —OC(O)N(R₁₈)—,—N(R₁₈)SO₂—, —SO₂N(R₁₈)—, —C(O)—O—, —O—C(O)—, —S—, —S(O)—, —S(O₂)—,—N(R₁₈)SO₂N(R₁₉)—,

wherein R₁₇, R₁₈, R₁₉ and R₂₀, independently comprise: -hydrogen,-alkyl, -aryl, -arylene-alkyl, -alkylene-aryl, or-alkylene-arylene-alkyl; and wherein the alkyl, aryl, heteroaryl,alkylene, and arylene groups in Ar₁, Ar₂, G, R₁-R₂₁, may be optionallysubstituted 1 to 4 times with a substituent group, wherein saidsubstituent group(s) or the term substituted refers to groupscomprising: a) -hydrogen; b) -fluoro; c) -chloro; d) -bromo; e) -iodo;f) -cyano; g) -nitro; h) -perfluoroalkyl; i) -Q-R₂₂; j) -Q-alkyl; k)-Q-aryl; l) -Q-alkylene-aryl; m) -Q-alkylene-NR₂₃R₂₄; or n)-Q-alkyl-W—R₂₅; wherein Q and W independently comprise: —CH₂—, —O—,—N(R₂₆)—, —C(O)—, —CON(R₂₆)—, —N(R₂₆)C(O)—, —N(R₂₆)CON(R₂₇)—,—N(R₂₆)C(O)—, —OC(O)N(R₂₆)—, —N(R₂₆)SO₂—, —SO₂N(R₂₆)—, —C(O)—O—,—O—C(O)—, or —N(R₂₆)SO₂N(R₂₇)—, wherein R₂₂, R₂₃, R₂₄, R₂₅, R₂₆ and R₂₇,independently comprise: -hydrogen, -alkyl, -aryl, -arylene-alkyl,-alkylene-aryl, or -alkylene-arylene-alkyl.
 2. The compound of Formula(I) in claim 1, wherein c is equal to 0 or
 1. 3. The compound of Formula(I) in claim 1, wherein c is equal to
 0. 4. The compound of Formula (I)in claim 1, wherein G comprises: -hydrogen, —CO₂R₁, —C(O)NR₁R₂, or—C(O)R₁, wherein R₁ and R₂ independently comprise: -hydrogen, -alkyl,-alkenyl, -aryl.
 5. The compound of Formula (I) in claim 1, wherein Gcomprises an ester isostere comprising the substituted oxadiazole:

wherein R₇ comprises alkyl, aryl, alkylene-sulfonyl-alkyl oralkylene-sulfonyl-aryl.
 6. The compound of Formula (I) in claim 5,wherein R₇ comprises an alkyl group.
 7. The compound of Formula (I) inclaim 1, wherein G comprises: -hydrogen.
 8. The compound of Formula (I)in claim 1, wherein G comprises: —CO₂R₁ wherein R₁ comprises alkyl. 9.The compound of Formula (I) in claim 1, wherein V comprises:—(CH₂)_(a)—, —(CH₂)_(b)—O—(CH₂)_(a)—, or a direct bond, wherein a isequal to 1 or 2, and b is equal to
 1. 10. The compound of Formula (I) inclaim 1, wherein V comprises: —(CH₂)_(a)— or a direct bond, wherein a isequal to
 1. 11. The compound of Formula (I) in claim 1, wherein Xcomprises: —N(R₉)—, —CON(R₉)—, —N(R₉)CO—, or —N(R₉)CON(R₁₀)—, wherein R₉and R₁₀ independently comprise: -hydrogen, -alkyl, -aryl,-arylene-alkyl, -alkylene-aryl, or -alkylene-arylene-alkyl.
 12. Thecompound of Formula (I) in claim 1, wherein X comprises: —N(R₉)—,—CON(R₉)—, or —N(R₉)CO—, wherein R₉ comprises: -hydrogen, -alkyl, -aryl,-arylene-alkyl, -alkylene-aryl, or -alkylene-arylene-alkyl.
 13. Thecompound of Formula (I) in claim 1, wherein X comprises —CON(R₉)—,wherein R₉ comprises: -hydrogen.
 14. The compound of Formula (I) inclaim 1, wherein Ar₁ comprises a mono- or bicyclic aryl or heteroarylgroup optionally substituted 1 to 7 times.
 15. The compound of Formula(I) in claim 1, wherein Ar, comprises a phenyl group having 1 to 5substituents, wherein the substituents independently comprise: a)-fluoro; b) -chloro; c) -bromo; d) -iodo; e) -cyano; D -nitro; g)-perfluoroalkyl; h) -D-R₁₂; i) -alkyl; j) -aryl; k) -heteroaryl; l)-heterocyclyl; m) -cycloalkyl; n) -alkylene-aryl; O)-alkylene-arylene-aryl; p) -alkylene-arylene-alkyl; q) -arylene-alkyl;r) -arylene-arylene-alkyl; s) -D-alkyl; t) -D-aryl; u) -D-alkylene-aryl;v) -D-arylene-alkyl; w) -D-alkylene-arylene-aryl; x)-D-arylene-arylene-aryl; y) -D-alkylene-arylene-alkyl; z)-alkylene-D-alkylene-aryl; aa) -arylene-D-alkyl; bb) -alkylene-D-aryl;cc) -alkylene-D-heteroaryl; dd) -alkylene-D-cycloalkyl; ee)-alkylene-D-heterocyclyl; ff) -alkylene-D-arylene-alkyl; gg)-alkylene-D-alkylene-arylene-alkyl; hh) -alkylene-D-alkyl; ii)-alkylene-D-R₁₃; jj) -arylene-D-R₁₃; or kk) -hydrogen; wherein Dcomprises —CH₂—, —O—, —N(R₁₄)—, —C(O)—, —CON(R₁₄)—, —N(R₁₄)C(O)—,—N(R₁₄)CON(R₁₅)—, —N(R₁₄)C(O)O—, —OC(O)N(R₁₄)—, —N(R₁₄)SO₂—,—SO₂N(R₁₄)—, —C(O)—O—, —O—C(O)—, —S—, —S(O)—, —S(O₂)—,—N(R₁₄)SO₂N(R₁₅)—,

wherein R₁₃, R₁₄, R₁₅, and R₁₆ independently comprise: -hydrogen,hydroxyl, -cyano, nitro, -alkyl, -aryl, -arylene-alkyl, -alkylene-aryl,or -alkylene-arylene-alkyl.
 16. The compound of Formula (I) in claim 1,wherein Ar, comprises a mono-substituted phenyl group wherein thesubstituent comprises: -aryl, -arylene-alkyl, -D-aryl,-D-alkylene-arylene-alkyl, or -arylene-D-alkyl; wherein D comprises —O—,—N(R₁₄)—, —CON(R₁₄)—, or —N(R₁₄)C(O)—, wherein R₁₄ comprises: -hydrogen;-alkyl; or -aryl.
 17. The compound of Formula (I) in claim 1, whereinAr, comprises: 2′-(4-tert-butyl-phenoxy)-biphenyl-4-yl,2′-(4-trifluoromethyl-phenoxy)-biphenyl-4-yl, 2′-phenoxy-biphenyl-4-yl,2′-trifluoromethyl-biphenyl-4-yl, 3′,4′-dichloro-biphenyl-4-yl,3′,4′-difluoro-biphenyl-4-yl, 3′,5′-bis-trifluoromethyl-biphenyl-4-yl,3,5′-difluoro-biphenyl-4-yl,3′-chloro-4′-fluoro-6-methoxy-biphenyl-3-yl,3′-chloro-4′-fluoro-biphenyl-2-yl, 3′-chloro-4′-fluoro-biphenyl-3-yl,3′-chloro-4′-fluoro-biphenyl-4-yl, 3′-chloro-biphenyl-4-yl,3′-nitro-biphenyl-4-yl, 3′-trifluoromethoxy-biphenyl-4-yl,3′-trifluoromethyl-biphenyl-4-yl, 4′-benzyloxy-3′-fluoro-biphenyl-4-yl,4-benzyloxy-phenyl, 4′-chloro-biphenyl-4-yl, 4′-fluoro-biphenyl-4-yl,4′-methanesulfonyl-biphenyl-4-yl, 4-naphthalen-2-yl-phenyl,4′-nitro-biphenyl-4-yl, 4′-phenoxy-biphenyl-4-yl,4-pyridin-3-yl-phenyl4′-tert-butyl-biphenyl-4-yl,4′-trifluoromethyl-biphenyl-4-yl, 6-methoxy-4′-nitro-biphenyl-3-yl,biphenyl, biphenyl-4-yl, chlorofluorophenoxy-phenyl, or(cyano-phenoxy)-phenyl.
 18. The compound of Formula (I) in claim 1,wherein Ar, comprises: [2-(4-Chloro-phenyl)-ethoxy]-phenyl,(4-nitro-phenoxy)-phenyl, (3-phenyl-propylamino)-phenyl,4-methoxy-4′-nitro-biphenyl-3-yl,(4′-methanesulfonyl-4-methoxy-biphenyl-3-yl), or(4′-methanesulfonyl-4-hydroxy-biphenyl-3-yl).
 19. The compound ofFormula (I) in claim 1, wherein Ar₁ comprises an unsubstituted biphenylgroup.
 20. The compound of Formula (I) in claim 1, wherein Ar₁ comprisesa biphenyl group substituted with at least one of the following groupsfluoro, chloro, trifluoroalkyl, trifluoroalkoxy, nitro, benzyloxy,phenoxy, and alkylsulfonyl.
 21. The compound of Formula (I) in claim 1,wherein Ar₂ comprises a substituted phenyl, 2-naphthyl, 2-pyridyl,3-isoquinolyl, 2-pyrimidyl or 2-quinazolyl group having 1 to 5substituents independently comprising: a) -fluoro; b) -chloro; c)-bromo; d) -iodo; e) -cyano; f) -nitro; g) -perfluoroalkyl; h) -T-R₁₇;i) -alkyl; j) -aryl; k) -arylene-alkyl; l) -T-alkyl; m)-T-alkylene-aryl; n) -T-alkylene-arylene-aryl; o)-T-alkylene-arylene-alkyl; or p) -arylene-T-alkyl; wherein T comprises—CH₂—, —O—, —N(R₁₈)—, —CON(R₁₈)—, or —N(R₁₈)C(O)—; wherein R₁₇, and R₁₈,independently comprise: -hydrogen, -alkyl, or -aryl.
 22. The compound ofFormula (I) in claim 1, wherein Ar₂ comprises:3′-chloro-4′-fluoro-4-hydroxy-biphenyl,2-hydroxy-5-[2-(4′-trifluoromethyl-biphenyl-3-yl)-acetylamino]-phenyl,2-hydroxy-5-pyridin-3-yl-phenyl, 3′,5′-difluoro-4-hydroxy-biphenyl,3′-chloro-4′-fluoro-4-hydroxy-biphenyl, 3′-fluoro-4-hydroxy-biphenyl,3′-trifluoromethyl-biphenyl-4-yl,4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl,4′-amino-4-hydroxy-biphenyl, 4′-fluoro-4-hydroxy-biphenyl,4-Hydroxy-2′-trifluoromethyl-biphenyl,4-hydroxy-3′,5′-bis-trifluoromethyl-biphenyl,4-hydroxy-3′-nitro-biphenyl, 4-hydroxy-4′-trifluoromethoxy-biphenyl,4-hydroxy-4′-trifluoromethyl-biphenyl, 4-hydroxy-biphenyl,5-benzo[1,3]dioxol-5-yl-2-hydroxy-phenyl, 5-bromo-2-hydroxy-phenyl,5-chloro-4-hydroxy-4′-trifluoromethyl-biphenyl,5-fluoro-4-hydroxy-4′-trifluoromethyl-biphenyl, or6-benzyloxy-4-hydroxy-4′-trifluoromethyl-biphenyl.
 23. The compound ofFormula (I) in claim 1, wherein Ar₂ comprises:3′-chloro-4′-fluoro-4-hydroxy-biphenyl, or4-hydroxy-4′-trifluoromethyl-biphenyl.
 24. The compound of Formula (I)in claim 1, wherein Ar₂ comprises:[2-(3,4-bis-benzyloxy-benzyloxy)-benzyloxy]-5-bromo-phenyl,2-(4-tert-butyl-benzyloxy)-5-chlorophenyl,3-bromo-5-chloro-2,6-dimethoxy-phenyl,4-(4-tert-butyl-benzyloxy)-4′-trifluoromethyl-biphenyl,4-acetoxy-2-phenyl-4′-trifluoromethyl-biphenyl,4-acetoxy-4′-trifluoromethyl-biphenyl,4-amino-4′-trifluoromethyl-biphenyl,4-butoxy-3′-chloro-4′-fluoro-biphenyl,4-methanesulfonylamino-4′-trifluoromethyl-biphenyl,4-methoxy-4′-trifluoromethyl-biphenyl,5-bromo-2-(4-[1,2,4]triazol-1-yl-benzyloxy)-phenyl,5-bromo-2-(4-tert-butyl-benzyloxy)-phenyl,5-bromo-2-cyclohexyloxy-phenyl, 5-bromo-2-heptyloxy-phenyl,5-chloro-2,4-dimethoxy-4′-trifluoromethyl-biphenyl,5-chloro-2-heptyloxy-phenyl.
 25. The compound of Formula (I) in claim 1,wherein Ar₂ comprises: 5-bromo-2-(3-pyridin-4-yl-propoxy)-phenyl,5-bromo-2-[2-(2-oxo-pyrrolidin-1-yl)-ethoxy]-phenyl,5-bromo-2-(2-morpholin-4-yl-ethoxy)-phenyl,5-bromo-2-(4,4,4-trifluoro-butoxy)-phenyl, or5-Bromo-2-(2-piperidin-1-yl-ethoxy)-phenyl.
 26. The compound of Formula(I) in claim 1, wherein Ar₂ comprises: 3-hydroxy-naphthalene.
 27. Thecompound of Formula (I) in claim 1, wherein Ar₂ comprises: a phenyl orbiphenyl group containing a hydroxy, alkyloxy, or acetoxy group ortho tothe Ar₂ group's point of attachment to X.
 28. The compound of Formula(I) in claim 1, wherein Ar₂ comprises: a phenyl or biphenyl groupcontaining a hydroxy, alkyloxy, or acetoxy group ortho to the Ar₂group's point of attachment to X and further substituted with at leastone of the following groups fluoro, chloro, trifluoroalkyl,trifluoroalkoxy, nitro, benzyloxy, phenoxy, phenyl, and alkylsulfonyl.29. The compound of Formula (I) in claim 1 comprising:3-Biphenyl-4-yl-(2S)-[(3′-chloro-4′-fluoro-4-hydroxy-biphenyl-3-carbonyl)-amino]-propionic acid methyl ester,3-Biphenyl-4-yl-2-(S)-[(3-hydroxy-naphthalene-2-carbonyl)-amino]-propionicacid methyl ester,2-(2S)-[(4-Hydroxy-4′-trifluoromethyl-biphenyl-3-carbonyl)-amino]-3-(4′-nitro-biphenyl-4-yl)-propionicacid methyl ester,2-(2S)-(5-Benzo[1,3]dioxol-5-yl-2-hydroxy-benzoylamino)-3-biphenyl-4-yl-propionicacid methyl ester,2-(S)-[(4-Hydroxy-4′-fluoro-biphenyl-3-carbonyl)-amino]-3-biphenyl-4-yl)propionicacid methyl ester,3-(3′,5′-Bis-trifluoromethyl-biphenyl-4-yl)-2-(2S)-[(3′-chloro-4′-fluoro-4-hydroxy-biphenyl-3-carbonyl)-amino]-propionicacid methyl ester,2-(S)-[(4-Hydroxy-4′-trifluoromethyl-biphenyl-3-carbonyl)-amino]-3-(4′-trifluoromethyl-biphenyl-4-yl)propionicacid methyl ester,2-(S)-[(4-Hydroxy-3′-trifluoromethyl-biphenyl-3-carbonyl)-amino]-3-(4′-trifluoromethyl-biphenyl-4-yl)-propionicacid methyl ester,3-(3′-Chloro-4′-fluoro-biphenyl-4-yl)-2-(S)-[(4-hydroxy-3′-trifluoromethyl-biphenyl-3-carbonyl)-amino]-propionicacid methyl ester,2-(S)-[(4-Hydroxy-3′-trifluoromethyl-biphenyl-3-carbonyl)-amino]-3-(2′-trifluoromethyl-biphenyl-4-yl)-propionicacid methyl ester,2-(S)-(5-Chloro-2-hydroxy-benzoylamino)-3-(2′-phenoxy-biphenyl-4-yl)-propionicacid methyl ester,2-(S)-(5-Bromo-2-hydroxy-benzoylamino)-3-(4′-phenoxy-biphenyl-4-yl)-propionicacid methyl ester, 4-Hydroxy-4′-trifluoromethyl-biphenyl-3-carboxylicacid [2-(3′-chloro-4′-fluoro-6-methoxy-biphenyl-3-yl)-ethyl]-amide,2-(S)-[(4-Acetoxy-4′-trifluoromethyl-biphenyl-3-carbonyl)-amino]-3-(3′-chloro-4′-fluoro-biphenyl-4-yl)-propionicacid methyl ester, 4-Hydroxy-4′-trifluoromethyl-biphenyl-3-carboxylicacid[1-(3′-chloro-4′-fluoro-biphenyl-4-ylmethyl)-2-(S)-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-amide,4-Hydroxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid[2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide,4-Hydroxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid[1-(R)-(3′-chloro-4′-fluoro-biphenyl-4-ylmethyl)-2-oxo-propyl]-amide,4-Hydroxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid[2-(4′-benzyloxy-3′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide,4-Hydroxy-4′-nitro-biphenyl-3-carboxylic acid[2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide,4-Hydroxy-3′,5′-bis-trifluoromethyl-biphenyl-3-carboxylic acid[2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide,4-Hydroxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid[2-(4′-methanesulfonyl-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide,Acetic acid3-[2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethylcarbamoyl]-4′-trifluoromethyl-biphenyl-4-ylester, 6-Benzyloxy-4-hydroxy-4′-trifluoromethyl-biphenyl-3-carboxylicacid[2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide,5-Bromo-N-[2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-2-hydroxy-benzamide,4-Hydroxy-3′;5′-bis-trifluoromethyl-biphenyl-3-carboxylic acid[2-biphenyl-4-yl-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide,4-Hydroxy-3′,5′-bis-trifluoromethyl-biphenyl-3-carboxylic acid[2-(4′-methanesulfonyl-biphenyl-4-yl)-1-(R)-(-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide,Acetic acid5′-[2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)ethylcarbamoyl]-4-trifluoromethyl[1,1′;3′,1″]terphenyl-4′-yl ester5-Chloro-4-hydroxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid[2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide,4-Hydroxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid[2-(4-benzyloxy-phenyl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide,5-Fluoro-4-hydroxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid[2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide,4-Hydroxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid[2-[4-(3-chloro-4-fluoro-phenoxy)-phenyl]-1-(R)-(3-methyl1,2,4]oxadiazol-5-yl)-ethyl]-amide, 3-Hydroxy-naphthalene-2-carboxylicacid[2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide,3-Hydroxy-naphthalene-2-carboxylic acid[2-(4′-methanesulfonyl-4-methoxy-biphenyl-3-yl)-ethyl]-amide, or4-Hydroxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid[1(R)-(3-tert-butyl-[1,2,4]oxadiazol-5-y)-2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-ethyl]-amide.30. A pharmaceutical composition comprising a compound of Formula (I)

wherein c is equal to 0, 1, or 2; wherein the values of 0, 1, and 2comprise a direct bond, —CH₂—, and —CH₂—CH₂—, optionally substituted 1to 4 times with a substituent group, wherein said substituent group(s)or the term substituted refers to groups comprising: -alkyl, -aryl,-alkylene-aryl, -arylene-alkyl, -alkylene-arylene-alkyl, —O-alkyl,—O-aryl, or -hydroxyl; G comprises: -hydrogen, -alkyl, -heteroaryl,-aryl, -heterocyclycl, —CH═CH—CO₂R₁, —CO₂R₁, —CH₂OR₁, —CH₂SR, —C(O)—R₁,—C(O)NR₁R₂, —C(R₁)═N—O—R₂, —C(O)C(O)R₁, —C(O)C(O)NR₁R₂, an acidisostere, or an ester isostere; wherein R₁ and R₂ independentlycomprise: -hydrogen, -alkyl, -aryl, -alkenyl, -arylene-alkyl,-alkylene-aryl, -alkylene-arylene-alkyl, -heterocyclyl, or -heteroaryl;or when R₁ and R₂ are bonded to a nitrogen group in G, R₁ and R₂ may betaken together to form a ring having the formula—(CH₂)_(m)-Z₂-(CH₂)_(n)—, wherein m and n are, independently, 1, 2, 3,or 4 and Z₂ comprises —CH₂—, —C(O)—, —O—, —N(H)—, —S—, —S(O)—, —S(O₂)—,—CON(H)—, —NHC(O)—, —NHC(O)N(H)—, —NH(SO₂)—, —S(O₂)N(H)—, —(O)CO—,—NHS(O₂)NH—, —OC(O)—, —N(R₂₁)—, —N(C(O)R₂₁)—, —N(C(O)NHR₂₁)—,—N(S(O₂)NHR₂₁)—, —N(SO₂R₂₁)—, or —N(C(O)OR₂₁)—; wherein R₂₁ compriseshydrogen, aryl, alkyl, or alkylene-aryl; or R₂ comprises a substituentof the formula

wherein L₁ comprises a direct bond, alkylene, —O-alkylene-, alkylene-O—,—NH—C(O)—, —C(O)—NH— or —NH—C(O)—NH—; L₂ comprises alkyline, alkenyline,heteroaryline, aryline, or heterocyclyline; L₃ comprises —O—, —N(R₃)—,—C(O)—N(R₃)—, —C(O)—O—, —C(O)—, —N(R₃)—C(O)—N(R₄)—, —CH═CH—CO₂R₁,—C(O)R₁, —C(O)C(O)R₁, or —C(O)C(O)NR₁R₂; L₄ comprises hydrogen, alkyl,alkenyl, alkynyl, heterocyclyl, heteroaryl, or -alkylene-aryl; and L₅comprises hydrogen, alkyl, alkenyl, alkynyl, -akylene-aryl,-alkylene-heteroaryl, alkylene-O-alkylene-aryl,-alkylene-S-alkylene-aryl, -alkylene-O-alkyl, -alkylene-S-alkyl,-alkylene-NH₂, -alkylene-OH, -alkylene-SH, -alkylene-C(O)—OR₅,-alkylene-C(O)—NR₅R₆, -alkylene-NR₅R₆, -alkylene-N(R₅)—C(O)—R₆, or-alkylene-N(R₅)—S(O₂)—R₆; or

may be taken together to constitute a direct bond; wherein R₃, R₄, R₅,and R₆ independently comprise hydrogen, aryl, heteroaryl, alkyl,-alkylene-aryl, or, -alkylene-heteroaryl; V comprises:—(CH₂)_(b)—O—(CH₂)_(a)—, —(CH₂)_(b)—N(R₈)—(CH₂)_(a)—, —(CH₂)_(b)—O—,—(CH₂)_(b)—N(R₈), —(CH₂)_(a)—, —CH═CH—(CR₈)— or a direct bond; in whicha is equal to 0, 1, or 2, b is equal to 1 or 2, and R₈ comprises:-hydrogen, -alkyl, -aryl, -arylene-alkyl, -alkylene-aryl, or-alkylene-arylene-alkyl; wherein the —CH₂— groups may be optionallysubstituted 1 to 4 times with a substituent group comprising: -alkyl,-aryl, -alkylene-aryl, -arylene-alkyl, -alkylene-arylene-alkyl,—O-alkyl, —O-aryl, or -hydroxyl; X comprises: —N(R₉)—, —CON(R₉)—,—N(R₉)CO—, —N(R₉)CON(R₁₀)—, —OC(O)N(R₈)—, —SO₂N(R₉)—, —N(R₉)SO₂—, or—N(R₉)SO₂N(R₁₀)—; wherein R₉ and R₁₀ independently comprise: -hydrogen,-alkyl, -aryl, -arylene-alkyl, -alkylene-aryl, -alkylene-arylene-alkyl,or —(CH₂)_(d)Y—, wherein d is equal to 0, 1, or 2, wherein Y comprises:-hydrogen, —CO₂R₁₁, —CH₂)R₁₁, —C(O)—R₁₁, —C(O)NR₁₁R₁₂, —C(R₁₁)═N—O—R₁₂,—NR₁₁R₁₂, or an acid isostere; wherein R₁₁ and R₁₂ independentlycomprise: -hydrogen, -alkyl, -aryl, -arylene-alkyl, -alkylene-aryl,-alkylene-arylene-alkyl, -heterocyclyl, or -heteroaryl; Ar₁ comprises anaryl, heteroaryl, fused cycloalkylaryl, fused cycloalkylheteroaryl,fused heterocyclylaryl, or fused heterocyclylheteroaryl group optionallysubstituted 1 to 7 times, wherein the substitutents independentlycomprise: a) -fluoro; b) -chloro; c) -bromo; d) -iodo; e) -cyano; f)-nitro; g) -perfluoroalkyl; h) -D-R₁₂; i) -alkyl; j) -aryl; k)-heteroaryl; l) -heterocyclyl; m) -cycloalkyl; n) -alkylene-aryl; o)-alkylene-arylene-aryl; p) -alkylene-arylene-alkyl; q) -arylene-alkyl;r) -arylene-arylene-alkyl; s) -D-alkyl; t) -D-aryl; u) -D-alkylene-aryl;v) -D-arylene-alkyl; w) -D-alkylene-arylene-aryl; x)-D-arylene-arylene-aryl; y) -D-alkylene-arylene-alkyl; z)-alkylene-D-alkylene-aryl; aa) -arylene-D-alkyl; bb) -alkylene-D-aryl;cc) -alkylene-D-heteroaryl; dd) -alkylene-D-cycloalkyl; ee)-alkylene-D-heterocyclyl; ff) -alkylene-D-arylene-alkyl; gg)-alkylene-D-alkylene-arylene-alkyl; hh) -alkylene-D-alkyl; ii)-alkylene-D-R₁₃; jj) -arylene-D-R₁₃; or kk) -hydrogen; wherein Dcomprises —CH₂—, —O—, —N(R₁₄)—, —C(O)—, —CON(R₁₄)—, —N(R₁₄)C(O)—,—N(R₁₄)CON(R₁₅)—, —N(R₁₄)C(O)O—, —OC(O)N(R₁₄)—, —N(R₁₄)SO₂—,—SO₂N(R₁₄)—, —C(O)—O—, —O—C(O)—, —S—, —S(O)—, —S(O₂)—,—N(R₁₄)SO₂N(R₁₅)—,

wherein R₁₃, R₁₄, R₁₅, and R₁₆ independently comprise: -hydrogen,hydroxyl, -cyano, nitro, -alkyl, -aryl, -arylene-alkyl, -alkylene-aryl,or -alkylene-arylene-alkyl; and Ar₂ comprises an aryl or heteroarylgroup optionally substituted 1 to 7 times, wherein the substitutentsindependently comprise: a) -fluoro; b) -chloro; c) -bromo; d) -iodo; e)-cyano; f) -nitro; g) -perfluoroalkyl; h) -T-R₁₇; i) -alkyl; j) -aryl;k) -heteroaryl; l) -heterocyclyl; m) -cycloalkyl; n) -alkylene-aryl; o)-alkylene-arylene-aryl; p) -alkylene-arylene-alkyl; q) -arylene-alkyl;r) -arylene-arylene-alkyl; s) -T-alkyl; t) -T-aryl; u) -T-alkylene-aryl;v) -T-arylene-alkyl; w) -T-alkylene-arylene-aryl; x)-T-arylene-arylene-aryl; y) -T-alkylene-arylene-alkyl; z)-alkylene-T-alkylene-aryl; aa) -arylene-T-alkyl; bb) -alkylene-T-aryl;cc) -alkylene-T-heteroaryl; dd) -alkylene-T-cycloalkyl; ee)-alkylene-T-heterocyclyl; ff) -alkylene-T-arylene-alkyl; gg)-alkylene-T-alkylene-arylene-alkyl; hh) -alkylene-T-alkyl; ii)-alkylene-T-R₁₇; jj) -arylene-T-R₁₇; or kk)-T-alkylene-arylene-heteroaryl; ll) -T-alkylene-heterocyclyl; mm)-T-alkylene-heteroaryl; nn) -T-heteroaryl; oo) -T-fusedheterocyclylaryl; pp) -T-fused cycloalkylaryl; qq) -T-fusedarylcycloalkyl; rr) -T-fused fused heterocyclylaryl; ss) -T-fused fusedarylheterocyclyl; tt) -T-fused fused cycloalkylheteroaryl; uu) -T-fusedfused heteroarylcycloalkyl; vv) -T-fused heterocyclylheteroaryl; ww)-T-fused heteroarylheterocyclyl; or xx) -hydrogen; wherein T comprises adirect bond, —CH₂—, —O—, —N(R₁₈)—, —C(O)—, —CON(R₁₈)—, —N(R₁₈)C(O)—,—N(R₁₈)CON(R₁₉)—, —N(R₁₈)C(O)O—, —OC(O)N(R₁₈)—, —N(R₁₈)SO₂—,—SO₂N(R₁₈)—, —C(O)—O—, —O—C(O)—, —S—, —S(O)—, —S(O₂)—,—N(R₁₈)SO₂N(R₁₉)—,

wherein R₁₇, R₁₈, R₁₉ and R₂₀, independently comprise: -hydrogen,-alkyl, -aryl, -arylene-alkyl, -alkylene-aryl, or-alkylene-arylene-alkyl; and wherein the alkyl, aryl, heteroaryl,alkylene, and arylene groups in Ar₁, Ar₂, G, R₁-R₂₁, may be optionallysubstituted 1 to 4 times with a substituent group, wherein saidsubstituent group(s) or the term substituted refers to groupscomprising: a) -hydrogen; b) -fluoro; c) -chloro; d) -bromo; e) -iodo;f) -cyano; g) -nitro; h) -perfluoroalkyl; i) -Q-R₂₂; j) -Q-alkyl; k)-Q-aryl; l) -Q-alkylene-aryl; m) -Q-alkylene-NR₂₃R₂₄; or n)-Q-alkyl-W—R₂₅; wherein Q and W independently comprise: —CH₂—, —O—,—N(R₂₆)—, —C(O)—, —CON(R₂₆)—, —N(R₂₆)C(O)—, —N(R₂₆)CON(R₂₇)—,—N(R₂₆)C(O)O—, —OC(O)N(R₂₆)—, —N(R₂₆)SO₂—, —SO₂N(R₂₆)—, —C(O)—O—,—O—C(O)—, or —N(R₂₆)SO₂N(R₂₇)—, wherein R₂₂, R₂₃, R₂₄, R₂₅, R₂₆ and R₂₇,independently comprise: -hydrogen, -alkyl, -aryl, -arylene-alkyl,-alkylene-aryl, or -alkylene-arylene-alkyl.
 31. The pharmaceuticalcompostion of claim 30, comprising a therapeutically effective amount ofthe compound of Formula (I).
 32. The pharmaceutical composition of claim30, further comprising one or more pharmaceutically acceptable carriers,excipients, or diluents.
 33. The pharmaceutical composition of claim 30,wherein the compound of Formula (I) inhibits smallpox virus.
 34. Thepharmaceutical composition of claim 30, further comprising one or moreadditional therapeutic agents.
 35. The pharmaceutical composition ofclaim 30 in the form of an oral dosage.
 36. The pharmaceuticalcomposition of claim 30 in the form of a parenteral dosage unit.
 37. Thepharmaceutical composition of claim 30, wherein said compound of Formula(I) comprises a dose in a range from about 0.01 to 1,000 mg/kg of bodyweight per day.
 38. The pharmaceutical composition of claim 30, whereinsaid compound of Formula (I) comprises a dose in a range from about 0.1to 100 mg/kg of body weight per day.
 39. The pharmaceutical compositionof claim 30 wherein said compound of Formula (I) comprises a dose in arange from about 0.5 to 10 mg/kg of body weight per day.
 40. A methodcomprising administering to a subject the compound of Formula (I) inclaim
 1. 41. The method of claim 40, wherein the compound of Formula (I)comprises an amount sufficient to reduce a viral load in a subject. 42.The method of claim 40, wherein said compound of Formula (I) isadministered as a dose in a range from about 0.01 to 1,000 mg/kg of bodyweight per day.
 43. The method of claim 40, wherein said compound ofFormula (I) is administered as a dose in a range from about 0.1 to 100mg/kg of body weight per day.
 44. The method of claim 40, wherein saidcompound of Formula (I) is administered as a dose in a range from about0.5 to 10 mg/kg of body weight per day.
 45. A method for inhibitingpropagation of a virus comprising the method of claim
 40. 46. The methodof claim 45, wherein the virus comprises an orthopox virus.
 47. Themethod of claim 45, wherein the virus comprises smallpox, vacciniavirus, monkey pox, or cow pox.
 48. The method of claim 40, wherein saidcompound of Formula (I) is administered to said subject as apharmaceutical composition comprising a therapeutically effective amountof said compound of Formula (I) and one or more pharmaceuticallyacceptable carriers, excipients, or diluents.
 49. The method of claim48, wherein the compound of Formula (I) is administered with anotherantiviral agent.
 50. The method of claim 48, wherein the compound ofFormula (I) is administered in an amount sufficient to reduce a viralload in a subject.